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Abstracts

Cancer Chemotherapy

ABSTRACTS

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Genotoxicity of idarubicin and its modulation by vitamins C and E and amifostine.

Blasiak J, Gloc E, Wozniak K, Mlynarski W, Stolarska M, Skorski T, Majsterek I. Department of Molecular Genetics, University of Lodz, Banacha 12/16, Poland. januszb@biol.uni.lodz.pl

Chem Biol Interact 2002 Apr 20;140(1):1-18

Idarubicin is an anthracycline anticancer drug used in haematological malignancies. The main side effect of idarubicin is free-radicals based cardiotoxicity. Using the comet assay we showed that the drug at concentrations from the range 0.001 to 10 microM induced DNA damage in normal human lymphocytes, measured as the increase in percentage of DNA in the tail (% tail DNA). The effect was dose-dependent. Treated cells were able to recover within a 120-min incubation. Recognised cell protector, amifostine at 14 mM decreased the mean % tail DNA of the cells exposed to idarubicin at all tested concentrations of the drug. So did vitamin C at 10 microM, but vitamin E (alpha-tocopherol) at 50 microM increased the % tail DNA. Lymphocytes exposed to idarubicin and treated with endonuclease III, formamidopyrimidine-DNA glycosylase and 3-methyladenine-DNA glycosylase II, enzymes recognizing oxidized and alkylated bases, displayed greater extent of DNA damage than those not treated with these enzymes. Pretreatment of lymphocytes with nitrone spin traps, N-tert-butyl-alpha-phenylnitrone and alpha-(4-pyridil-1-oxide)-N-tert-butylnitrone decreased the extent of DNA damage evoked by idarubicin. To discuss the influence of vitamins and amifostine in cancer cells we used also murine pro-B lymphoid BaF3 transformed with BCR/ABL oncogene. These cells can be treated as model cells of human acute myelogenous leukemia. The response of these cells to vitamin E was quantitatively the same as human lymphocytes. However, vitamin C did not exert any effect on DNA damage and amifostine, in spite to normal lymphocytes, potentiated this effect. The results obtained suggest that reactive oxygen species, including free radicals, may be involved in the formation of DNA lesions induced by idarubicin. The drug can also methylate DNA bases. Our results indicate that not only cardiotoxicity but also genotoxicity and in consequence induction of secondary malignancies should be taken into account as diverse side effects of idarubicin. Amifostine may potentate DNA-damage effect of idarubicin in cancer cells and decrease this effect in normal cells. Vitamin C can be considered as protective agents against DNA damage in normal cells in persons receiving idarubicin-based chemotherapy, but the use of vitamin E cannot be recommended and at least needs further research.

Protective effect of coenzyme Q10 on anthracyclines cardiotoxicity: control study in children with acute lymphoblastic leukemia and non-Hodgkin lymphoma.

Iarussi D, Auricchio U, Agretto A, Murano A, Giuliano M, Casale F, Indolfi P, Iacono A. Medical-Surgery Institute of Cardiology, 2nd University of Naples, Italy.

Mol Aspects Med 1994;15 Suppl:s207-12

Two groups of children with acute lymphoblastic leukemia or non-Hodgkin lymphoma, treated with anthracyclines (ANT), were studied: group I, consisting of 10 patients, with coenzyme Q10 (CoQ) therapy; group II, consisting of 10 patients without CoQ therapy. The ANT cumulative dose was 240 +/- 20.0 mg/m2 in group I and 252.0 +/- 20.1 mg/m2 in group II. Echocardiographic study was performed at the beginning, at the cumulative dose of 180 mg/m2 and at the end of therapy with ANT. Percentage left ventricular fractional shortening (%LVFS) decreased from baseline (40.36 +/- 4.6) to end value (35.82 +/- 5.02) (P < 0.05) in group I; %LVFS decreased from baseline (39.89 +/- 4.37) to end value (33.43 +/- 3.46) (P < 0.002) in group II. Interventricular septum wall thickening decreased only in group II from baseline (46.10 +/- 10.1) to end therapy (27.00 +/- 18.54) (P < 0.01). Septum wall motion abnormalities were detected only in 2 patients of group II. These data demonstrate a protective effect of CoQ on cardiac function during therapy with ANT.

Inhibition by oral N-acetylcysteine of doxorubicin-induced clastogenicity and alopecia, and prevention of primary tumors and lung micrometastases in mice.

D'Agostini F, Bagnasco M, Giunciuglio D, Albini A, De Flora S. Institute of Hygiene and Preventive Medicine, University of Genoa, I-16132 Genoa, Italy.

Int J Oncol 1998 Aug;13(2):217-24

The thiol N-acetylcysteine (NAC), an analog and precursor of glutathione, displays cancer preventive properties not only in early stages of the carcinogenesis process but also in its advanced stages. NAC inhibited type-IV collagenase activity as well as invasion, tumor take, and metastasis of malignant cells in murine models. Previously, we provided evidence for synergistic effects of oral NAC with intravenously injected doxorubicin (DOX). In the present study B16-BL6 melanoma cells were injected s.c. into the footpad of C57BL/6 mice. The animals were divided into 5 groups: i) untreated mice; ii) mice receiving daily NAC with drinking water (12.25 mmol/kg body weight) starting 16 h after injection of cancer cells; iii) mice receiving a single i.v. injection of DOX (2 micromol/kg body weight) 24 h after injection of cancer cells; iv) mice receiving a combination of NAC and DOX, with NAC treatment starting 72 h before injection of cancer cells; and v) mice treated as in iv) but with NAC treatment starting 16 h after injection of cancer cells. Both NAC and DOX, either individually or in combination, significantly enhanced the survival time as compared to controls. The weight of local primary tumors was significantly decreased by either drug, and was further decreased to a significant extent, compared to the individual treatments, in the two groups of mice receiving combinations of NAC and DOX. No lung micrometastases, evaluated by immunohistochemistry as S-100-positive foci of melanocytic cells, were detectable in the two groups of mice receiving the combined treatments. NAC significantly, attenuated the time-related increase of micronucleated polychromatic erythrocytes in the peripheral blood of DOX-treated mice. All mice individually treated with DOX developed a partial but well evident alopecia, diffusely affecting their back hair, which was totally prevented by NAC, irrespective of the combination schedule. Thus, besides preventing DOX cardiotoxicity, as extensively documented in the literature, oral NAC protects mice from DOX-induced myelogenotoxicity and alopecia, and at the same time interacts with this cytotoxic agent in inhibiting cancer cell invasion and metastasis.

Synergism between N-acetylcysteine and doxorubicin in the prevention of tumorigenicity and metastasis in murine models.

De Flora S, D'Agostini F, Masiello L, Giunciuglio D, Albini A. Institute of Hygiene and Preventive Medicine, University of Genoa, Italy.

Int J Cancer 1996 Sep 17;67(6):842-8

The thiol N-acetylcysteine (NAC) is a promising cancer chemopreventive agent which acts through a variety of mechanisms, including its nucleophilic and antioxidant properties. We have recently shown that NAC inhibits type-IV collagenase activity as well as invasion, tumor take and metastasis of malignant cells in mice. NAC is also known to attenuate the cardiotoxicity of the cytostatic drug doxorubicin (DOX, Adriamycin). The present study was designed to evaluate whether the combination of NAC and DOX treatments in mice injected with cancer cells could affect their tumorigenic and metastatic properties. Six separate experiments were carried out, using a total of 291 adult female mice. In experimental metastasis assays, in which B16-F10 melanoma cells were injected i.v. into (CD-1)BR nude mice, DOX significantly reduced the number of lung metastases when administered i.v. at a dose of 10 mg/kg body weight, 3 days after the i.v. injection of cancer cells. NAC inhibited lung metastases when added to the medium of cancer cells before their i.v. injection. The combined treatment with DOX and NAC, under various experimental conditions, was highly effective, showing a synergistic reduction in the number of mestastases. In tumorigenicity and spontaneous metastasis assays, in which B16-BL6 melanoma cells were injected s.c. into the footpad of C57BL/6 mice, DOX decreased the number of lung metastases when given i.p. at 2 mg/kg body weight. Oral NAC exerted significant protective effects, and considerably prolonged survival of mice. The combined treatment with DOX and NAC again showed synergistic effects on the frequency and weight of primary tumors and local recurrences, and completely prevented the formation of lung metastases in the experiment in which these end-points were evaluated at fixed times. While injection of DOX 7 days after implantation of cancer cells failed to improve the cancer-protective effects of NAC, its injection after I day resulted in a striking inhibition of lung metastases. These findings demonstrate an evident synergism between DOX (given parenterally) and NAC (given with drinking water) in preventing tumorigenicity and metastases. The indications of these animal studies warrant further evaluation in clinical trials.

Chemopreventive effect of Ginkgo biloba extract against benzo(a)pyrene-induced forestomach carcinogenesis in mice: amelioration of doxorubicin cardiotoxicity.

Agha AM, El-Fattah AA, Al-Zuhair HH, Al-Rikabi AC. Dept. of Pharmacology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

J Exp Clin Cancer Res 2001 Mar;20(1):39-50

Ginkgo biloba extract (EGb) is a natural product that possesses antioxidant and anticlastogenic properties. The current study was conducted to investigate the effect of EGb on benzo(a)pyrene (BP)-induced forestomach neoplasia, and to explore its possible beneficial effects against doxorubicin (Dox)-induced cardiotoxicity. Tumor was induced in female Swiss albino mice by oral administration of 1 mg BP, twice weekly for four weeks. EGb was given, at a daily oral dose of 150 mg kg(-1), two weeks before and during BP administration. Dox was given ip at a dose of 1.5 mg kg(-1), once weekly, for four weeks, during BP administration. EGb and Dox were given as combined or monotherapies. Results of the present investigation revealed that EGb blunted forestomach tumor multiplicity, as compared to control tumor bearing group. It also exhibited high activity to induce cytosolic glutathione S-transferase and glucose-6-phosphate dehydrogenase (G6PDH) in liver, as well as replenished hepatic glutathione that have been inhibited or depleted by tumorigenesis. Furthermore, it normalized nitric oxide (NO) serum level, without any observed alteration in neither the activity of liver microsomal NADPH-cytochrome P-450 reductase nor serum level of tumor necrosis factor-alpha (TNFalpha). Similar results have been obtained with Dox, but it failed to affect G6PDH activity, while increased serum TNFalpha and NO levels. The combined therapy did not add further to the anticarcinogenic effect of Dox, however it succeeded in ameliorating the deleterious effects of Dox on the heart; as evidenced by the reduction of cardiac lipoperoxidation, with modulation of Dox-induced pathological changes. Therefore, EGb confers a beneficial chemopreventive effect against BP-induced gastric carcinogenesis in mice, and possesses a salutary ameliorating potential on the cardiotoxic effects of Dox.

Ginger syrup as an antiemetic in early pregnancy.

Keating A, Chez RA. Department of Obstetrics and Gynecology, University of South Florida, Tampa, USA.

Altern Ther Health Med 2002 Sep-Oct;8(5):89-91

CONTEXT: Ginger (Zingiber officinale) has been used to ameliorate symptoms of nausea. A beverage containing ginger in a syrup may be easier to consume than a capsule or solid food.

OBJECTIVE: To determine if ginger syrup mixed in water is an effective remedy for the relief of nausea and vomiting in the first trimester of pregnancy.

DESIGN: Double-blind, placebo-controlled, randomized clinical trial.

SETTING: Subjects were enrolled from the University of South Florida department of obstetrics and gynecology private practice office.

PATIENTS: 26 subjects in the first trimester of pregnancy.

INTERVENTION: Subjects ingested 1 tablespoon of commercially prepared study syrup (or placebo) in 4 to 8 ounces of hot or cold water 4 times daily.

MAIN OUTCOME MEASURES: Duration and severity of nausea and vomiting over a 2-week period measured on a 10-point scale.

RESULTS: After 9 days, 10 of the 13 (77%) subjects receiving ginger had at least a 4-point improvement on the nausea scale. Only 2 of the 10 (20%) remaining subjects in the placebo group had the same improvement. Conversely, no woman in the ginger group, but 7 (70%) of the women in the placebo group, had a 2-point or less improvement on the nausea scale. Eight of the 12 (67%) women in the ginger group who were vomiting daily at the beginning of the treatment stopped vomiting by day 6. Only 2 of the 10 (20%) women in the placebo group who were vomiting stopped by day 6.

CONCLUSION: The ingestion of 1 g of ginger in syrup in a divided dose daily may be useful in some patients experiencing nausea and vomiting in the first trimester of pregnancy.

The use of a whey protein concentrate in the treatment of patients with metastatic carcinoma: a phase I-II clinical study.

Kennedy RS, Konok GP, Bounous G, Baruchel S, Lee TD. Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada.

Anticancer Res 1995 Nov-Dec;15(6B):2643-9

Glutathione (GSH) concentration is high in most tumour cells and this may be an important factor in resistance to chemotherapy. Previous in-vitro and animal experiments have shown a differential response of tumour versus normal cells to various cysteine delivery systems. More specifically, an in-vitro assay showed that at concentrations that induce GSH synthesis in normal human cells, a specially prepared whey protein concentrate, Immunocal, caused GSH depletion and inhibition of proliferation in human breast cancer cells. On the basis of this information five patients with metastatic carcinoma of the breast, one of the pancreas and one of the liver were fed 30 grams of this whey protein concentrate daily for six months. In six patients the blood lymphocyte GSH levels were substantially above normal at the outset, reflecting high tumour GSH levels. Two patients (#1, #3) exhibited signs of tumour regression, normalization of haemoglobin and peripheral lymphocyte counts and a sustained drop of lymphocyte GSH levels towards normal. Two patients (#2, #7) showed stabilisation of the tumour, increased haemoglobin levels. In three patients (#4, #5, #6,) the disease progressed with a trend toward higher lymphocyte GSH levels. These results indicate that whey protein concentrate might deplete tumour cells of GSH and render them more vulnerable to chemotherapy.

Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status.

Lissoni P, Barni S, Mandala M, Ardizzoia A, Paolorossi F, Vaghi M, Longarini R, Malugani F, Tancini G. Division of Radiation Oncology, S. Gerardo Hospital, Monza, Milan, Italy.

Eur J Cancer 1999 Nov;35(12):1688-92

Melatonin (MLT) has been proven to counteract chemotherapy toxicity, by acting as an anti-oxidant agent, and to promote apoptosis of cancer cells, so enhancing chemotherapy cytotoxicity. The aim of this study was to evaluate the effects of concomitant MLT administration on toxicity and efficacy of several chemotherapeutic combinations in advanced cancer patients with poor clinical status. The study included 250 metastatic solid tumour patients (lung cancer, 104; breast cancer, 77; gastrointestinal tract neoplasms, 42; head and neck cancers, 27), who were randomized to receive MLT (20 mg/day orally every day) plus chemotherapy, or chemotherapy alone. Chemotherapy consisted of cisplatin (CDDP) plus etoposide or gemcitabine alone for lung cancer, doxorubicin alone, mitoxantrone alone or paclitaxel alone for breast cancer, 5-FU plus folinic acid for gastro-intestinal tumours and 5-FU plus CDDP for head and neck cancers. The 1-year survival rate and the objective tumour regression rate were significantly higher in patients concomitantly treated with MLT than in those who received chemotherapy (CT) alone (tumour response rate: 42/124 CT + MLT versus 19/126 CT only, P < 0.001; 1-year survival: 63/124 CT + MLT versus 29/126 CT only, P < 0.001). Moreover, the concomitant administration of MLT significantly reduced the frequency of thrombocytopenia, neurotoxicity, cardiotoxicity, stomatitis and asthenia. This study indicates that the pineal hormone MLT may enhance the efficacy of chemotherapy and reduce its toxicity, at least in advanced cancer patients of poor clinical status.

Is there a role for melatonin in supportive care?

Lissoni P. U.O. di Oncologia Medica e Radioterapia, Ospedale S. Gerardo dei Tintori, 20052 Monza (MI), Italy. oncologia@genie.it

Support Care Cancer 2002 Mar;10(2):110-6

Melatonin (MLT) is the main hormone released from the pineal gland and has proved to have physiological antitumor activity. MLT has been shown to exert anticancer activity through several biological mechanisms: antiproliferative action, stimulation of anticancer immunity, modulation of oncogene expression, and anti-inflammatory, anti-oxidant and anti-angiogenic effects. Several experimental studies have shown that MLT may inhibit cancer cell growth, and preliminary clinical studies seem to confirm its anticancer property in humans. In addition, MLT may have other biological effects, which could be useful in the palliative therapy of cancer, namely anticachectic, anti-asthenic and thrombopoietic activities. On this basis, the present clinical investigation was performed in an attempt at better definition of the therapeutic properties of MLT in human neoplasms. In a first clinical study, we evaluated the effects of MLT in a group of 1,440 patients with untreatable advanced solid tumors, who received supportive care alone or supportive care plus MLT. In a second study, we evaluated the influence of MLT on the efficacy and toxicity of chemotherapy in a group of 200 metastatic patients with chemotherapy-resistant tumor histotype, who were randomized to receive chemotherapy alone or chemotherapy plus MLT. In both studies, MLT was given orally at 20 mg/day during the dark period of the day. The frequency of cachexia, asthenia, thrombocytopenia and lymphocytopenia was significantly lower in patients treated with MLT than in those who received supportive care alone. Moreover, the percentage of patients with disease stabilization and the percentage 1-year survival were both significantly higher in patients concomitantly treated with MLT than in those treated with supportive care alone. The objective tumor response rate was significantly higher in patients treated with chemotherapy plus MLT than in those treated with chemotherapy alone. Moreover, MLT induced a significant decline in the frequency of chemotherapy-induced asthenia, thrombocytopenia, stomatitis, cardiotoxicity and neurotoxicity. These clinical results demonstrate that the pineal hormone MLT may be successfully administered in medical oncology in the supportive care of untreatable advanced cancer patients and for the prevention of chemotherapy-induced toxicity.

The clinical neuroimmunotherapeutic role of melatonin in oncology.

Conti A, Maestroni GJ. Centre for Experimental Pathology, Istituto Cantonale di Patologia, Locarno, Switzerland.

J Pineal Res 1995 Oct;19(3):103-10

In the past several years, interest in the immunophysiological role of the pineal gland and melatonin has grown to the extent that now their immunoregulatory role is widely recognized. Melatonin has immunoenhancing properties and it is able to counteract the immunodepression induced by acute stress, drug treatment (i.e., anticancer drugs), and viral infections. Here we review the therapeutic efficacy of melatonin alone or in combination with interleukin-2 (IL-2) in cancer patients who did not respond to standard anticancer chemotherapies and/or refused any aggressive treatment. In this review, we summarize a series of reports from 1986 through 1994 in which patients affected by metastatic solid tumors, metastatic non-small-cell lung cancer, advanced solid neoplasms, myelodysplastic syndrome, hepatocellular carcinoma, and advanced endocrine tumors were studied. The conclusion drawn from these studies is that melatonin protects against IL-2 and synergizes with the IL-2 anticancer action. This combined strategy represents a well tolerated intervention to control tumor growth. In most cases performance status and quality of life seem improved.

kappa-Opioid receptors in marrow stroma mediate the hematopoietic effects of melatonin-induced opioid cytokines.

Maestroni GJ. Center for Experimental Pathology, Istituto Cantonale di Patologia, Locarno, Switzerland.

Ann N Y Acad Sci 1998 May 1;840:411-9

Melatonin exerts colony-stimulating activity and rescues myeloid progenitors from apoptosis, induced either in vivo or in vitro by cancer chemotherapy compounds in tumor-bearing mice. These effects are mediated mainly by T-helper cell-derived opioid cytokines with an apparent molecular mass of 15 kDa and 67 kDa that are recognized both by anti-interleukin-4 and anti-dynorphin B antibodies. These putative new cytokines were named melatonin-induced-opioid (MIO). The most active and naltrexone-sensitive MIO was the smaller molecule, which was called MIO15 and found to act on an opioid-binding site present in adherent bone marrow cells. However, the hematopoietic action of MIO15 was dependent on the presence of colony-stimulating factors (CSF). To investigate this point, we studied the ability of melatonin to rescue granulocyte/macrophage colony-forming units (GM-CFU) in the bone marrow of tumor-free animals treated with cancer chemotherapeutic compounds. We found that melatonin not only is unable to protect bone marrow GM-CFU unless the mice are transplanted with Lewis lung carcinoma (LLC), but also that melatonin seems to increase the myelotoxicity of cyclophosphamide in tumor-free mice. In both tumor-bearing or healthy mice, the effect of melatonin is negated by naltrexone, indicating the involvement of MIO15. Competition studies classified the target opioid-binding site as a kappa-opioid receptor with low affinity in tumor-free mice and high affinity in LLC-implanted mice. LLC is known to release CSF. Consistently, addition of CSF in the form of lung-conditioned medium (LCM) to adherent bone marrow cells increased the affinity of the kappa-opioid receptor. Addition of antigranulocyte/macrophage colony-stimulating factor (GM-CSF) mAbs neutralized the effect of LCM. In conclusion, the affinity state of the kappa-opioid receptors in stromal bone marrow cells seems to modulate the hematopoietic effect of melatonin and/or MIO15.

Colony-stimulating activity and hematopoietic rescue from cancer chemotherapy compounds are induced by melatonin via endogenous interleukin 4.

Maestroni GJ, Conti A, Lissoni P. Center for Experimental Pathology, Istituto cantonale di Patologia, Locarno, Switzerland.

Cancer Res 1994 Sep 1;54(17):4740-3

We have reported that melatonin may rescue bone marrow cells from apoptosis induced either in vivo or in vitro by cancer chemotherapy compounds via bone marrow T-cells and endogenous release of granulocyte-macrophage colony-stimulating factor. Here we show that the number of granulocyte/macrophage colony-forming units cultured with suboptimal concentrations of colony-stimulating factor was higher in the presence of melatonin both at physiological and pharmacological concentrations. CD4+,Thy-1.2+ cell depletion or addition of anti-mouse interleukin 4 monoclonal antibodies prevented both effects of melatonin. Upon incubation with etoposide, the concentration of myeloid precursors was 43 +/- 8 per 10(5) cells. The melatonin+etoposide value was 68 +/- 7, whereas that of melatonin+etoposide+anti-interleukin 4 was 38 +/- 6. Melatonin was also ineffective when bone marrow cells were separated in adherent and nonadherent populations. Supernatants from nonadherent cells incubated with melatonin proved to contain interleukin 4 activity which, however, showed its influence on unseparated bone marrow and adherent cells but not on nonadherent cells. It is proposed that melatonin represents a neuroendocrine regulator of interleukin 4 production in bone marrow T-helper cells. Interleukin 4 may then stimulate adherent stromal cells to produce granulocyte/macrophage colony-stimulating factor. Such a neuroendocrine-cytokine mechanism may explain the hematopoietic rescue of melatonin as well as its antitumoral and immunoenhancing properties.

Hematopoietic rescue via T-cell-dependent, endogenous granulocyte-macrophage colony-stimulating factor induced by the pineal neurohormone melatonin in tumor-bearing mice.

Maestroni GJ, Covacci V, Conti A. Center for Experimental Pathology, Istituto Cantonale di Patologia, Locarno, Switzerland.

Cancer Res 1994 May 1;54(9):2429-32

We investigated whether melatonin can affect tumor growth and/or hematopoiesis in mice transplanted with Lewis lung carcinoma and treated with cyclophosphamide or etoposide. These agents were injected i.p. for 5 days at two different cumulative doses (cyclophosphamide, 40 and 160 mg/kg body weight; etoposide, 20 and 40 mg/kg body weight) from day 8 through day 12 after tumor transplantation. Melatonin was injected s.c. at a dose of 1 mg/kg body weight/day, from day 8 throughout the experiments and from days 8 through 12 or from day 13 onwards. Melatonin did not influence tumor growth but selectively counteracted bone marrow toxicity when administered together with the cancer chemotherapy compounds without interfering with their anticancer action. In vitro, melatonin proved to counteract apoptosis in bone marrow cells incubated with etoposide. Such protection was reflected by an increased frequency of granulocyte/macrophage-colony forming units but not of the pluripotent spleen-colony forming units. The effect of melatonin was neutralized by anti-granulocyte/macrophage-colony-stimulating factor monoclonal antibodies. When athymic, T-cell-deficient mice were used as bone marrow donors, melatonin did not exert any protective effect. This suggested that melatonin is able to stimulate the endogenous production of granulocyte/macrophage-colony-stimulating factor via bone marrow T-cells. Due to the well known lack of toxic and undesirable side effects of melatonin, these findings might have a straightforward clinical application.

Clinical and non-invasive assessment of anthracycline cardiotoxicity: perspectives on myocardial protection.

Mortensen SA, Aabo K, Jonsson T, Baandrup U.

Int J Clin Pharmacol Res 1986;6(2):137-50

A series of 38 patients with solid tumours (N=29) and haematological malignancies (N=9) and with suspicion of cardiotoxicity (CTX) due to antineoplastic drugs was studied. The series comprised 22 females and 16 males (mean age 52 years). The patients were examined clinically by ECG, chest X-ray and echocardiography. Seventeen patients were classified as having moderate or severe chronic CTX; 16 patients developed either arrhythmias shortly after the administration of chemotherapy (acute CTX) or arrhythmias and/or signs of myocardial dysfunction (without overt congestive heart failure) at a later date, after chemotherapy had been suspended (latent CTX). In 5 cases the suspicion of CTX could not be confirmed. Weak and non-specific symptoms such as unexplained tachycardia or coughing at night should alert the clinician and result in ECG control and further non-invasive cardiological investigations (including radionuclide angiocardiography) before additional anthracycline is administered. Chest X-ray is a very insensitive method with respect to early diagnosis of chronic CTX; in cases of doubt heart catheterization with endomyocardial biopsy should be carried out to obtain a reliable estimate of the extent of morphological damage. As anthracycline CTX may present without prominent clinical symptoms or as latent disease, one should be aware of potential precipitating factors such as volume load (during i.v. chemotherapy), surgical trauma and general anaesthesia and alcohol abuse. Further effects to lessen CTX should be made, using supposed cardio-protective substances in randomized clinical trials. Promising research on coenzyme Q10 and carnitine may usher in a new era in the prevention of anthracycline cardiotoxicity.

Modification of the effect of tamoxifen, cis-platin, DTIC, and interferon-alpha 2b on human melanoma cells in culture by a mixture of vitamins.

Prasad KN, Hernandez C, Edwards-Prasad J, Nelson J, Borus T, Robinson WA. Department of Radiology, University of Colorado Health Sciences Center, Denver 80262.

Nutr Cancer 1994;22(3):233-45

The effect of a mixture of vitamins in modifying the efficacy of commonly used drugs in the treatment of human melanoma has not been studied. Vitamin C and d-alpha-tocopheryl succinate (alpha-TS) alone reduced the growth of human melanoma (SK-30) cells in culture, whereas beta-carotene (BC), 13-cis-retinoic acid (RA), or sodium selenite alone was ineffective. RA caused morphological changes, as evidenced by flattening of cells and formation of short cytoplasmic processes. A mixture of four vitamins (vitamin C, BC, alpha-TS, and RA) was more effective in reducing growth of human melanoma cells than a mixture of three vitamins. The growth-inhibitory effect of cis-platin, decarbazine, tamoxifen, and recombinant interferon-alpha 2b was enhanced by vitamin C alone, a mixture of three vitamins (BC, alpha-TS, and RA), and a mixture of four vitamins (vitamin C, BC, alpha-TS, and RA) that contained 50 micrograms/ml of vitamin C. These data show that a mixture of three or four vitamins can enhance the growth-inhibitory effect of currently used chemotherapeutic agents on human melanoma cells.

Scientific rationale for using high-dose multiple micronutrients as an adjunct to standard and experimental cancer therapies.

Prasad KN, Cole WC, Kumar B, Prasad KC. Center for Vitamins and Cancer Research, Department of Radiology, School of Medicine, University of Colorado Health Sciences Center, Denver 80262, USA. Kedar.prasad@UCHSC.edu

J Am Coll Nutr 2001 Oct;20(5 Suppl):450S-463S; discussion 473S-475S

We have hypothesized that high-dose multiple micronutrients, including antioxidants, as an adjunct to standard (radiation therapy and chemotherapy) or experimental therapy (hyperthermia and immunotherapy), may improve the efficacy of cancer therapy by increasing tumor response and decreasing toxicity. Several in vitro studies and some in vivo investigations support this hypothesis. A second hypothesis is that antioxidants may interfere with the efficacy of radiation therapy and chemotherapy. This hypothesis is based on the concept that antioxidants will destroy free radicals that are generated during therapy, thereby protecting cancer cells against death. None of the published data on the effect of antioxidants in combination with radiation or chemotherapeutic agents on tumor cells supports the second hypothesis. Scientific rationale in support of a micronutrient protocol to be used as an adjunct to standard or experimental cancer therapy is presented.

High doses of multiple antioxidant vitamins: essential ingredients in improving the efficacy of standard cancer therapy.

Prasad KN, Kumar A, Kochupillai V, Cole WC. Center for Vitamins and Cancer Research, Department of Radiology, School of Medicine, University of Colorado Health Sciences Center, Denver 80262, USA.

J Am Coll Nutr 1999 Feb;18(1):13-25

Numerous articles and several reviews have been published on the role of antioxidants, and diet and lifestyle modifications in cancer prevention. However, the potential role of these factors in the management of human cancer have been largely ignored. Extensive in vitro studies and limited in vivo studies have revealed that individual antioxidants such as vitamin A (retinoids), vitamin E (primarily alpha-tocopheryl succinate), vitamin C (primarily sodium ascorbate) and carotenoids (primarily polar carotenoids) induce cell differentiation and growth inhibition to various degrees in rodent and human cancer cells by complex mechanisms. The proposed mechanisms for these effects include inhibition of protein kinase C activity, prostaglandin E1-stimulated adenylate cyclase activity, expression of c-myc, H-ras, and a transcription factor (E2F), and induction of transforming growth factor-beta and p21 genes. Furthermore, antioxidant vitamins individually or in combination enhance the growth-inhibitory effects of x-irradiation, chemotherapeutic agents, hyperthermia, and biological response modifiers on tumor cells, primarily in vitro. These vitamins, individually, also reduce the toxicity of several standard tumor therapeutic agents on normal cells. Low fat and high fiber diets can further enhance the efficacy of standard cancer therapeutic agents; the proposed mechanisms for these effects include the production of increased levels of butyric acid and binding of potential mutagens in the gastrointestinal tract by high fiber and reduced levels of growth promoting agents such as prostaglandins, certain fatty acids and estrogen by low fat. We propose, therefore, a working hypothesis that multiple antioxidant vitamin supplements together with diet and lifestyle modifications may improve the efficacy of standard and experimental cancer therapies.

Glutathione in the prevention of cisplatin induced toxicities. A prospectively randomized pilot trial in patients with head and neck cancer and non small cell lung cancer.

Schmidinger M, Budinsky AC, Wenzel C, Piribauer M, Brix R, Kautzky M, Oder W, Locker GJ, Zielinski CC, Steger GG. Division of Oncology, Boltzmann Institute for Experimental Oncology, Austria. Manuela.schmidinger@a-topmail.at

Wien Klin Wochenschr 2000 Jul 28;112(14):617-23

PURPOSE: Glutathione has been shown to be an effective chemoprotector against cisplatin-induced side effects in patients with ovarian cancer. In view of this fact, we performed a randomized clinical pilot-trial in the management of other solid tumors in order to compare application of Glutathione to intensive hydration in patients undergoing chemotherapy with a regimen including cisplatin.

PATIENTS AND METHODS: Twenty patients suffering from advanced non small cell lung cancer (n = 6) or head- and neck cancer (n = 14) were enrolled in the study. All patients received 80 mg/m2 cisplatin along with etoposide or 5-fluorouracil every 4 weeks. Patients randomized to application of Glutathione (n = 11) received 5 g of Glutathione immediately before application of cisplatin followed by 2000 ml of normal saline. Patients in the control group (n = 9) received 2000 ml electrolyte infusion before and 2000 ml of normal saline with forced diuresis after cisplatin.

RESULTS: The intensity of hematologic toxicity was significantly less pronounced in patients treated with Glutathione than in the control group (hemoglobin: 10.7 vs 9.5 mg% respectively, p = 0.039; white blood cell count 3.3 vs 2.2 x 103/microliter respectively, p = 0.004; platelets 167 vs 95 x 103/microliter respectively, p = 0.02), whereas in terms of non-hematologic toxicity no difference was observed. Objective remission occurred in 6 out of 11 evaluable patients from the group receiving Glutathione (55%; complete remission: 9%; partial remission: 46%), and in 4 out of 8 evaluable patients from the control group (partial remission: 50%). However, there was no statistical difference in terms of response and overall survival (13.5 months vs. 10.5 months) between the two groups.

CONCLUSIONS: Application of Cisplatin and Glutathione seems to be safe and feasible and the antitumoral efficacy of cisplatin is apparently not impaired by the concomitant use of Glutathione in patients with solid tumors.

[Chronic cardiotoxicity of anthracycline derivatives and possible prevention by coenzyme Q10] [Article in Japanese]

Tajima M.

Gan No Rinsho 1984 Jul;30(9 Suppl):1211-6

Adriamycin (ADR), one of the anthracycline derivatives, has the most strong cardiotoxicity. We studied the cardiotoxicity caused by ADR in New Zealand white rabbits and its protection by the medication of CoQ10. The findings of ECG and the myocardial tissue examined by the electron microscope showed the effectiveness of the injection of CoQ10 to prevent the cardiotoxicity caused by ADR. The concomitant injection of CoQ10 dissolved in saline was tried in patients with various kinds of neoplasm who were given more than 200 mg of ADR or DM. Only one patient showed the ST-T change. On the contrary, 3 of patients given more than 200 mg ADR or DM alone showed abnormal change of ECG.

Enhancement of the activity of doxorubicin by inhibition of glutamate transporter.

Sadzuka Y, Sugiyama T, Suzuki T, Sonobe T. School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, 422-8526, Shizuoka, Japan. sadzuka@u-shizuoka-ken.ac.jp

Toxicol Lett 2001 Sep 15;123(2-3):159-67

Theanine enhanced doxorubicin (DOX) induced antitumor activity by increasing the concentration of DOX in the tumor through the inibition of efflux of DOX from tumor cells. As theanine reduced the level of glutamate via suppression of the glutamate transporter in tumor cells, we studied the change in the intracellular concentration of glutathione (GSH) and the correlation with the GSH S-conjugate export (GS-X) pump. The reduction in the concentration of glutamate in tumor cells caused by theanine, induced decreases in the intracellular GSH and GS-DOX levels. The expression of MRP5 in M5076 cells, was confirmed. We concluded that the GS-DOX conjugate was transported extracellularly via the MRP5/GS-X pump in M5076 cells and that theanine affected this route. Namely, theanine increases the concentration of DOX in a tumor in vivo through inhibition of the glutamate transporter via the GS-X pump.

Cardioprotection in patients undergoing chemo- and/or radiotherapy for neoplastic disease.

A pilot study. Wagdi P, Fluri M, Aeschbacher B, Fikrle A, Meier B. Department of Cardiology, University Hospital, Bern, Switzerland.

Jpn Heart J 1996 May;37(3):353-9

OBJECTIVES: To assess the cardioprotective efficiency of an antioxidant regimen (vitamins E, C and N-acetylcysteine) in patients receiving high dose chemo- and/or radiotherapy for malignant disease.

METHODS: Prospective, placebo controlled, randomized and double blinded pilot study involving 13 patients receiving chemotherapy and 12 patients receiving radiotherapy.

RESULTS: In patients receiving antioxidants, left ventricular ejection fraction did not change (63 +/- 4% to 63 +/- 4%). In the placebo group, ejection fraction changed from 67 +/- 6% to 61 +/- 4% (p = 0.03). No patient in the antioxidant group and 6/13 (46%) patients in the placebo group showed a fall of > 10% in the left ventricular ejection fraction. In the chemotherapy group, the left ventricular ejection fraction changed from 62% (+/- 2) to 63% (+/- 2) in the patients treated with antioxidants (ns) and from 63% (+/- 5) to 61% (+/- 5) in patients treated with placebo (ns). No patient showed a significant fall in ejection fraction in the antioxidant group, whereas 2/7 (29%) in the placebo group showed a reduction > or = 10%. In the radiotherapy group, left ventricular ejection fraction did not change inverted question mark64% (+/- 6) to 64% (+/- 5) inverted question mark in patients treated with antioxidants (ns) and changed from 70% (+/- 8) to 60% (+/- 4) in patients treated with placebo (p = 0.008). No patient in the antioxidant group, but 4/6 (66%) patients in the placebo group showed a fall of > or = 10% in ejection fraction.

CONCLUSION: The small number of patients in the study precludes a definitive statement. The preliminary results however suggest efficient cardioprotection by this nontoxic and inexpensive antioxidant combination, so larger studies are warranted for confirmation.

ZD1839 (Iressa): An Orally Active Inhibitor of Epidermal Growth Factor Signaling with Potential for Cancer Therapy.

Wakeling AE, Guy SP, Woodburn JR, Ashton SE, Curry BJ, Barker AJ, Gibson KH. Department of Cancer and Infection Research, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.

Cancer Res 2002 Oct 15;62(20):5749-54

The epidermal growth factor receptor (EGFR) is a promising target for anticancer therapy because of its role in tumor growth, metastasis and angiogenesis, and tumor resistance to chemotherapy and radiotherapy. We have developed a low-molecular-weight EGFR tyrosine kinase inhibitor (EGFR-TKI), ZD1839 (Iressa(2) ). ZD1839, a substituted anilinoquinazoline, is a potent EGFR-TKI (IC(50) = 0.033 micro M) that selectively inhibits EGF-stimulated tumor cell growth (IC(50) = 0.054 micro M) and that blocks EGF-stimulated EGFR autophosphorylation in tumor cells. In studies with mice bearing a range of human tumor-derived xenografts, ZD1839 given p.o. once a day inhibited tumor growth in a dose-dependent manner. The level of expression of EGFR did not determine xenograft tumor sensitivity to ZD1839. Long-term ZD1839 (>3 months) treatment of mice bearing A431 xenografts was well tolerated, and ZD1839 completely inhibited tumor growth and induced regression of established tumors. No drug-resistant tumors appeared during ZD1839 treatment, but some tumors regrew after drug withdrawal. These studies indicate the potential utility of ZD1839 in the treatment of many human tumors and indicate that continuous once-a-day p.o. dosing might be a suitable therapeutic regimen.

Epidermal growth factor receptor dependence in human tumors: more than just expression?

Arteaga CL. Departments of Medicine and Cancer Biology, and Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Oncologist 2002;7 Suppl 4:31-9

The epidermal growth factor receptor (EGFR) is a rational target for antitumor strategies. EGFR signaling causes increased proliferation, decreased apoptosis, and enhanced tumor cell motility and neo-angiogenesis. The EGFR is expressed or highly expressed in a variety of human tumors of epithelial origin. ZD1839 (Iressa(TM)) is an orally active, selective EGFR tyrosine kinase inhibitor, which blocks signal transduction pathways implicated in proliferation and survival of cancer cells. The lack of a consistent method of evaluating levels of EGFR has caused a disparity in reports of the EGFR as a prognostic factor; however, for some tumors, EGFR is a strong prognostic indicator associated with more aggressive disease and reduced survival. So far, no clear association between EGFR levels and response to EGFR-targeted agents has been found. Preclinical studies with ZD1839 have noted a relationship between the two in some cases, but not others. EGFR signaling may be increased by a number of mechanisms in addition to high expression levels of EGFR, including receptor mutations, heterodimerization with other members of this receptor family such as HER2 (erbB2), increased expression of (autocrine/ paracrine) ligands, and alterations in molecules that control receptor signaling output. Each of these components could be assessed to give an indication of the magnitude of EGFR signal amplification. Evaluation of signaling components downstream from EGFR should provide information on the activation of the EGFR pathway. Until EGFR-based assays predictive of a response to receptor-targeted therapies are available, there is no clear justification for stratifying patients by EGFR status or excluding patients with low EGFR levels from trials with ZD1839 or other EGFR inhibitors.

Granulocyte-macrophage colony-stimulating factor treatment before doxorubicin and cyclophosphamide chemotherapy priming in women with early-stage breast cancer.

Kobrinsky NL; Sjolander DE; Cheang MS; Levitt R; Steen PD MeritCare Roger Maris Cancer Center, Fargo, ND 58122, USA.

J Clin Oncol 1999 Nov;17(11):3426-30

PURPOSE: To determine if inhibition of stem-cell activity induced by granulocyte-macrophage colony-stimulating factor ([GM-CSF]; Sargramostim; Immunex Corporation, Seattle, WA) withdrawal or priming protects hematopoietic stem cells from the cytotoxic effects of adjuvant chemotherapy for early-stage breast cancer.

PATIENTS AND METHODS: Serial blood counts were performed in 20 women with early-stage breast cancer receiving four courses of cyclophosphamide and doxorubicin chemotherapy. By a double-blind, placebo-controlled, balanced randomization, subjects received GM-CSF priming on days 5 to 1 for courses 1 and 3 or courses 2 and 4. RESULTS: Compared with before priming, after priming the times to neutrophil nadir (12.8 +/- 2.5 days v 14.8 +/- 1.5 days, respectively; P =.0001) and platelet nadir (mean +/- SD, 10.1 +/- 1.9 days v 11.1 +/- 2.2 days, P <.05) were shorter, indicating a shift of cytotoxicity to later progenitors. The neutrophil nadir was similar with and without priming (mean +/- SD, 490 +/- 310/microL v 550 +/- 350/microL, respectively; P =.2); however, on day 16 the mean neutrophil count was higher (mean +/- SD, 1030 +/- 580/microL v 690 +/- 370/microL, P =.004), and the proportion of patients with a neutrophil count less than 500/microL was lower after priming than before (six of 35 or 17. 1% v 12 of 34 or 35.3%, respectively; P =.04). The platelet nadir was higher (mean +/- SD, 166,000 +/- 51,000/microL after priming v 151,000 +/- 45,000/microL before priming, P =.007), and the duration of thrombocytopenia, ie, a platelet count less than 150,000/microL, was shorter (1.5 +/- 2.1 days v 2.8 +/- 2.9 days, P =.0025) after priming. Episodes of fever and neutropenia were not observed.

CONCLUSIONS: GM-CSF priming from days 5 to 1 before doxorubicin and cyclophosphamide chemotherapy was associated with an earlier neutrophil and platelet nadir. On day 16, a higher mean neutrophil count and a lower proportion of patients with severe (< 500/microL) neutropenia were observed. Beneficial effects on the severity and duration of thrombocytopenia were also noted. These observations support the hypothesis that GM-CSF priming protects hematopoietic progenitors from the cytotoxic effects of chemotherapy.

The effect of cimetidine on the pharmacokinetics of epirubicin in patients with advanced breast cancer: preliminary evidence of a potentially common drug interaction.

Murray LS, Jodrell DI, Morrison JG, Cook A, Kerr DJ, Whiting B, Kaye SB, Cassidy J. University of Glasgow, Western Infirmary, UK.

Clin Oncol (R Coll Radiol) 1998;10(1):35-8

Epirubicin is known to be metabolized in the liver. Therefore, drugs such as cimetidine, which inhibit the cytochrome P-450 enzyme system or reduce liver blood flow, may reduce the plasma clearance of epirubicin. In a small study, epirubicin 100 mg/m2 every 3 weeks was administered intravenously to eight patients, who also received oral cimetidine (400 mg b.d. for 7 days starting 5 days before chemotherapy) with either the first or second cycles. Epirubicin pharmacokinetics and liver blood flow (idocyanine green clearance) were assessed at each course. The areas under the plasma concentration time curves (AUCs) were used to compare the systemic exposure to epirubicin and its metabolites with each course. The estimated median percentage increase (95% confidence interval CI) in the AUC with cimetidine were: epirubicin 50% (95% CI -18 to 193, epirubicinol 41% (95% CI 1 to 92). Despite the small numbers studied, the increase in the active metabolite epirubicinol was significant (P < 0.05). These changes in exposure were not explained by reduced cytochrome P-450 activity as the 7-deoxy-doxorubicinol aglycone AUC was not reduced (357% increase: 95% CI 17 to 719) or by a decrease in liver blood flow (17% increase: 95% CI -39 to 104). Cimetidine is likely to be coprescribed or self-administered with epirubicin and therefore clinicians should be aware of this potential interaction.

Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells.

Matsumoto S, Imaeda Y, Umemoto S, Kobayashi K, Suzuki H, Okamoto T.Department of Surgery, Second Teaching Hospital, School of Medicine, Fujita Health University, 3-6-10 Otohbashi, Nakagawa-ku, Nagoya 454-8509, Japan. smatsumo@fujita-hu.ac.jp

Br J Cancer 2002 Jan 21;86(2):161-7

Cimetidine has been shown to have beneficial effects in colorectal cancer patients. In this study, a total of 64 colorectal cancer patients who received curative operation were examined for the effects of cimetidine treatment on survival and recurrence. The cimetidine group was given 800 mg day(-1) of cimetidine orally together with 200 mg day(-1) of 5-fluorouracil, while the control group received 5-fluorouracil alone. The treatment was initiated 2 weeks after the operation and terminated after 1 year. Robust beneficial effects of cimetidine were noted: the 10-year survival rate of the cimetidine group was 84.6% whereas that of control group was 49.8% (P<0.0001). According to our previous observations that cimetidine blocked the expression of E-selectin on vascular endothelium and inhibited the adhesion of cancer cells to the endothelium, we have further stratified the patients according to the expression levels of sialyl Lewis antigens X (sL(x)) and A (sL(a)). We found that cimetidine treatment was particularly effective in patients whose tumour had higher sL(x) and sL(a) antigen levels. For example, the 10-year cumulative survival rate of the cimetidine group with higher CSLEX staining, recognizing sL(x), of tumours was 95.5%, whereas that of control group was 35.1% (P=0.0001). In contrast, in the group of patients with no or low levels CSLEX staining, cimetidine did not show significant beneficial effect (the 10-year survival rate of the cimetidine group was 70.0% and that of control group was 85.7% (P=n.s.)). These results clearly indicate that cimetidine treatment dramatically improved survival in colorectal cancer patients with tumour cells expressing high levels of sL(x) and sL(a). Copyright 2002 The Cancer Research Campaign

Differential effects of polyunsaturated fatty acids on chemosensitivity of NIH3T3 cells and its transformants.

Tsai WS, Nagawa H, Muto T. First Department of Surgery, Graduate School of Medicine, University of Tokyo, Japan.

Int J Cancer 1997 Jan 27;70(3):357-61

Polyunsaturated fatty acids (PUFAs) have been suggested, on the basis of animal-model studies, to be related not only to cancer development but also to chemotherapeutic effects. Controversy persists, however, as to which types of PUFAs are beneficial in terms of chemosensitivity. In this study, we used the NIH3T3 cell line and its SIC(sigmoid colon cancer)-oncogene transformants to investigate the effects of PUFAs on the chemosensitivity of non-malignant and malignant cells in terms of cell proliferation. We also determined the fatty-acid composition of cells by high-performance liquid chromatography (HPLC). The results revealed that the sensitivity of SIC transformants to mitomycin C (MC) was lower than that of NIH3T3 cells cultured in 10% calf-serum DMEM without PUFA supplementation. When cells were cultured in DMEM supplemented with eicosapentaenoic acid (EPA) at a concentration (2 micrograms/ml) that does not influence cell proliferation, the sensitivity of SIC transformants to MC increased, whereas that of NIH3T3 cells decreased in comparison with the sensitivity of cells cultured without PUFA supplementation (p < 0.05). There was no difference between the 2 cell lines in the chemosensitivity of cells cultured in medium supplemented with arachidonic acid (ARA). The SIC transformants contained more stearic acid (C:18) and less lauric acid (C:12) than NIH3T3 cells cultured without PUFA. Culturing the cells in medium supplemented with EPA or ARA modified the cellular fatty-acid composition. EPA caused the relative combined percentage of lauric acid and myristic acid (C:14) in SIC transformants to decrease significantly, and the SIC transformants tended to accumulate additional EPA, in contrast to the NIH3T3 cells. We conclude that the alterations in fatty-acid composition in malignant transformants caused by exogenous EPA differ from those in non-malignant cells, and that these changes account for the increased chemosensitivity of malignant transformants. Although preliminary, these findings imply that EPA specifically enhances the chemosensitivity of malignant cells.

Effect of fish oil, arginine, and doxorubicin chemotherapy on remission and survival time for dogs with lymphoma: a double-blind, randomized placebo-controlled study.

Ogilvie GK, Fettman MJ, Mallinckrodt CH, Walton JA, Hansen RA, Davenport DJ, Gross KL, Richardson KL, Rogers Q, Hand MS. Comparative Oncology Unit, Departments of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.

Cancer 2000 Apr 15;88(8):1916-28

BACKGROUND: Polyunsaturated n-3 fatty acids have been shown to inhibit the growth and metastasis of tumors. This double-blind, randomized study was designed to evaluate the hypothesis that polyunsaturated n-3 fatty acids can improve metabolic parameters, decrease chemical indices of inflammation, enhance quality of life, and extend disease free interval and survival time for dogs treated for lymphoblastic lymphoma with doxorubicin chemotherapy.METHODS: Thirty-two dogs with lymphoma were randomized to receive one of two diets supplemented with menhaden fish oil and arginine (experimental diet) or an otherwise identical diet supplemented with soybean oil (control diet). Diets were fed before and after remission was attained with up to five dosages of doxorubicin. Parameters examined included blood concentrations of glucose, lactic acid, and insulin in response to glucose and diet tolerance tests; alpha-1 acid glycoprotein; tumor necrosis factor; interleukin-6; body weight; amino acid profiles; resting energy expenditure; disease free interval (DFI); survival time (ST); and clinical performance scores.

RESULTS: Dogs fed the experimental diet had significantly (P < 0.05) higher mean serum levels of the n-3 fatty acids docosahexaenoic acid (C22:6) and eicosapentaenoic acid (C20:5) compared with controls. Higher serum levels of C22:6 and C20:5 were associated with lesser (P < 0.05) plasma lactic acid responses to intravenous glucose and diet tolerance testing. Increasing C22:6 levels were significantly (P < 0.05) associated with longer DFI and ST for dogs with Stage III lymphoma fed the experimental diet.

CONCLUSIONS: Fatty acids of the n-3 series normalize elevated blood lactic acid in a dose-dependent manner, resulting in an increase in DFI and ST for dogs with lymphoma. Copyright 2000 American Cancer Society.

Caffeine-increased radiosensitivity is not dependent on a loss of G2/M arrest or apoptosis in bladder cancer cell lines.

Ribeiro JC, Barnetson AR, Jackson P, Ow K, Links M, Russell PJ. Oncology Research Centre, The Prince of Wales Hospital and Department of Medicine, The University of New South Wales, Randwick, Australia.

Int J Radiat Biol 1999 Apr;75(4):481-92

PURPOSE: Bladder cancer cell lines UCRU-BL-13, UCRU-BL-17/2 and UCRU-BL-28, with differing p53 status and molecular responses to irradiation, were used to investigate possible mechanisms for caffeine-induced radiosensitization.

MATERIALS AND METHODS: After treatment with caffeine and exposure to X-radiation, radiosensitivity was determined by clonogenic assay. Cell-cycle arrest and apoptosis were measured by flow cytometry.

RESULTS: Both BL-13 and BL-28 cells (each expressing p53 with a wild-type sequence) fail to arrest at the G2 checkpoint after radiation, but nevertheless caffeine did induce radiosensitization. In contrast, in BL-17/2 cells (expressing p53 with a point mutation in codon 280), caffeine treatment abrogated the radiation-induced G2 arrest but was not accompanied by radiosensitization. No effects on radiosensitivity were seen in RT112 cells (expressing a functionally defective p53) at low caffeine doses (2 mM), but at higher doses (4 mM and 10 mM) caffeine caused both abrogation of radiation-induced G2 arrest and radiosensitization. In none of the cell lines examined did caffeine treatment and/or irradiation result in apoptosis.

CONCLUSIONS: In contrast with previous studies, the data suggest that radiosensitization induced by caffeine is not dependent on abrogation of G2 arrest or the induction of apoptosis, and is not selective for cells expressing p53 proteins with mutations.

Effects of oral administration of tea, decaffeinated tea, and caffeine on the formation and growth of tumors in high-risk SKH-1 mice previously treated with ultraviolet B light.

Lou YR, Lu YP, Xie JG, Huang MT, Conney AH Department of Chemical Biology, College of Pharmacy, Rutgers, State University of New Jersey, Piscataway 08854-8020, USA.

Nutr Cancer 1999;33(2):146-53

Treatment of SKH-1 mice with ultraviolet B light (UV-B, 30 mJ/cm2) twice a week for 22-23 weeks resulted in tumor-free animals with a high risk of developing malignant and nonmalignant tumors during the next several months in the absence of further UV-B treatment (high-risk mice). In three separate experiments, oral administration of green tea or black tea (4-6 mg tea solids/ml) as the sole source of drinking fluid for 18-23 weeks to these high-risk mice inhibited the formation and decreased the size of nonmalignant squamous cell papillomas and keratoacanthomas as well as the formation and size of malignant squamous cell carcinomas. In one experiment all these inhibitory effects of tea were statistically significant, whereas in the two other experiments many but not all of the inhibitory effects of tea were statistically significant. The decaffeinated teas were inactive or less effective inhibitors of tumor formation than the regular teas, and adding caffeine back to the decaffeinated teas restored biological activity. Oral administration of caffeine alone (0.44 mg/ml) as the sole source of drinking fluid for 18-23 weeks inhibited the formation of nonmalignant and malignant tumors, and this treatment also decreased tumor size in these high-risk mice.

Caffeine inhibits the checkpoint kinase ATM.

Blasina A, Price BD, Turenne GA, McGowan CH. Department of Molecular Biology The Scripps Research Institute La Jolla, California, 92037, USA.

Curr Biol 1999 Oct 7;9(19):1135-8

The basis of many anti-cancer therapies is the use of genotoxic agents that damage DNA and thus kill dividing cells. Agents that cause cells to override the DNA-damage checkpoint are predicted to sensitize cells to killing by genotoxic agents. They have therefore been sought as adjuncts in radiation therapy and chemotherapy. One such compound, caffeine, uncouples cell-cycle progression from the replication and repair of DNA [1] [2]. Caffeine therefore servers as a model compound in establishing the principle that agents that override DNA-damage checkpoints can be used to sensitize cells to the killing effects of genotoxic drugs [3]. But despite more than 20 years of use, the molecular mechanisms by which caffeine affects the cell cycle and checkpoint responses have not been identified. We investigated the effects of caffeine on the G2/M DNA-damage checkpoint in human cells. We report that the radiation-induced activation of the kinase Cds1 [4] (also known as Chk2 [5]) is inhibited by caffeine in vivo and that ATM kinase activity is directly inhibited by caffeine in vitro. Inhibition of ATM provides a molecular explanation of the attenuation of DNA-damage checkpoint responses and for the increased radiosensitivity of caffeine-treated cells [6] [7] [8].

Variation in sensitizing effect of caffeine in human tumour cell lines after gamma-irradiation.

Valenzuela MT, Mateos S, Ruiz de Almodovar JM, McMillan TJ. Laboratoio de Investigaciones Medicas y Biologia Tumoral, Departamento de Radiologia y Medicina Fisica, Facultad de Medicina, Universidad de Granada, 18071, Granada, Spain.

Radiother Oncol 2000 Mar;54(3):261-71

BACKGROUND AND PURPOSE: We have investigated whether the protective role of the G2 checkpoint has increasing importance when the p53-dependent G1 checkpoint is inactivated.

MATERIALS AND METHODS: We have studied the differential effect of caffeine by clonogenic assays and flow cytometry in three human tumour cell lines with different functionality of p53 protein.

RESULTS: The radiosensitizing effect of caffeine (2 mM) expressed itself as a significant decrease in surviving fraction at 2 Gy and a significant increase in alpha-values in RT112 and TE671, both with non-functional p53. However, no radiosensitizing effect was seen in cells with a normal p53 function (MCF-7 BUS). Two millimoles of caffeine also caused important changes in the cell cycle progression after irradiation. MCF-7 BUS showed a G1 arrest after irradiation and an early G2 arrest but those cells that reached the second G2 did not arrest significantly. In contrast, TE671 exhibited radiosensitization by caffeine, no G1 arrest, a G2 arrest in those cells irradiated in G2, no significant accumulation in the second G2 but an overall delay in release from the first cell cycle, which could be abrogated by caffeine. RT112 was similar to TE671 except that the emphasis in a G2 arrest was shifted from the block in cells irradiated in G2 to those irradiated at other cell cycle phases. CONCLUSION: The data presented confirm that p53 status can be a significant determinant of the efficacy of caffeine as radiosensitizer in these tumour cell lines, and document the importance of the G2 checkpoint in this effect.

Structure-activity relationships for G2 checkpoint inhibition by caffeine analogs.

Jiang X, Lim LY, Daly JW, Li AH, Jacobson KA, Roberge M. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.

Int J Oncol 2000 May;16(5):971-8

Caffeine inhibits the G2 checkpoint activated by DNA damage and enhances the toxicity of DNA-damaging agents towards p53-defective cancer cells. The relationship between structure and G2 checkpoint inhibition was determined for 56 caffeine analogs. Replacement of the methyl group at position 3 or 7 resulted in loss of activity, while replacement at position 1 by ethyl or propyl increased activity slightly. 8-Substituted caffeines retained activity, but were relatively insoluble. The structure-activity profile did not resemble those for other known pharmacological activities of caffeine. The active analogs also potentiated the killing of p53-defective cells by ionizing radiation, but none was as effective as caffeine.

 

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