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LE Magazine December 2000

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Cancer Prevention

Inhibitory effect of curcumin on epidermal growth factor receptor kinase activity in A431 cells

We explored the mechanism of antigrowth action of Curcumin by investigating its effect on epidermal growth factor (EGF) receptor intrinsic kinase activity in the human epidermoid carcinoma A431 cells. The short-term treatment of cells with Curcumin inhibited EGF receptor intrinsic kinase activity up to 90% in a dose- and time-dependent manner, and also inhibited EGF-induced tyrosine phosphorylation of EGF receptors. The observed early effects of Curcumin were mediated via a cellular mechanism(s), and preceded the period when inhibition of cell growth occurred.

Biochim Biophys Acta 1994 Dec 30;1224(3):597-600

Inhibition of ligand-induced activation of epidermal growth factor receptor tyrosine phosphorylation by curcumin

We explored the regulation of epidermal growth factor (EGF)-mediated activation of EGF receptor (EGF-R) phosphorylation by curcumin (diferuloyl-methane), a recently identified kinase inhibitor, in cultured NIH 3T3 cells expressing human EGF-R. Treatment of cells with a saturating concentration of EGF for 5-15 min induced increased EGF-R tyrosine phosphorylation by 4- to 11-fold and this was inhibited in a dose- and time-dependent manner by up to 90% by curcumin, which also inhibited the growth of EGF-stimulated cells. There was no effect of curcumin treatment on the amount of surface expression of labeled EGF-R and inhibition of EGF-mediated tyrosine phosphorylation of EGF-R by curcumin was mediated by a reversible mechanism. In addition, curcumin also inhibited EGF-induced, but not bradykinin-induced, calcium release. These findings demonstrate that curcumin is a potent inhibitor of a growth stimulatory pathway, the ligand-induced activation of EGF-R, and may potentially be useful in developing anti-proliferative strategies to control tumor cell growth.

Carcinogenesis 1995 Aug;16(8):1741-5

New agents for cancer chemoprevention

Clinical chemoprevention trials of more than 30 agents and agent combinations are now in progress or being planned. The most advanced agents are well known and are in large Phase III chemoprevention intervention trials or epidemiological studies. These drugs include several retinoids [e.g., retinol, retinyl palmitate, all-trans-retinoic acid, and 13-cis-retinoic acid], calcium, Beta carotene, vitamin E, tamoxifen, and finasteride. Other newer agents are currently being evaluated in or being considered for Phase II and early Phase III chemoprevention trials. Prominent in this group are all-trans-N-(4-hydroxy phenyl) retinamide (4-HPR) (alone and in combination with tamoxifen), 2-difluoromethylornithine (DFMO), nonsteroidal anti-inflammatory drugs (aspirin, piroxicam, sulindac), oltipraz, and dehydroepiandrostenedione (DHEA). A third group is new agents showing chemopreventive activity in animal models, epidemiological studies, or in pilot clinical intervention studies. They are now in preclinical toxicology testing or Phase I safety and pharmacokinetics trials preparatory to chemoprevention efficacy trials. These agents include S-allyl-l-cysteine, curcumin, DHEA analog 8354 (fluasterone), genistein, ibuprofen, indole-3-carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, sulindac sulfone, tea extracts, ursodiol, vitamin D analogs, and p-xylyl selenocyanate. A new generation of agents and agent combinations will soon enter clinical chemoprevention studies based primarily on promising chemopreventive activity in animal models and in mechanistic studies. Among these agents are more efficacious analogs of known chemopreventive drugs including novel carotenoids (e.g., alpha-carotene and lutein). Also included are safer analogs which retain the chemopreventive efficacy of the parent drug such as vitamin D3 analogs. Other agents of high interest are aromatase inhibitors (e.g., (+)-vorozole), and protease inhibitors (e.g., Bowman-Birk soybean trypsin inhibitor). Combinations are also being considered, such as vitamin E with l-selenomethionine. Analysis of signal transduction pathways is beginning to yield classes of potentially active and selective chemopreventive drugs. Examples are ras isoprenylation and epidermal growth factor receptor inhibitors.

J Cell Biochem Suppl 1996;26:1-28

Therapeutic potential of curcumin in human prostate cancer. II. Curcumin inhibits tyrosine kinase activity of epidermal growth factor receptor and depletes the protein

Purpose: In a search for alternative and preventive therapies for prostate cancer, attention was focused on the ways in which curcumin (Turmeric), used in food and medicine in India for centuries, could interfere with the growth factor signaling pathways in both androgen-dependent and androgen-independent prostate cancer cells, as exemplified by the epidermal growth factor receptor (EGF-R) signaling. Materials and Methods: The androgen-sensitive LNCaP and androgen-insensitive PC-3 cell lines were grown in 5 to 50 &mgr;M curcumin and analyzed for EGF-R protein by Western blotting and for EGF-R tyrosine kinase activity. Results: Curcumin was a potent inhibitor of EGF-R signaling, and it accomplished this effect by three different means (1) down regulating the EGF-R protein; (2) inhibiting the intrinsic EGF-R tyrosine kinase activity; and (3) inhibiting the ligand-induced activation of the EGF-R. Conclusions: These results, taken together with our previous results that curcumin can induce apoptosis in both androgen-dependent and androgen-independent prostate cancer cells, support our view that curcumin may be a novel modality by which one can interfere with the signal transduction pathways of the prostate cancer cell and prevent it from progressing to its hormone-refractory state.

Mol Urol 2000 Spring;4(1):1-6

The role of induction chemotherapy in the curative treatment of squamous cell cancer of the head and neck

Induction chemotherapy is appropriate for the treatment of locally advanced squamous cell carcinoma of the head and neck because it allows organ preservation without compromising survival and improves survival in unresectable disease. Radiation therapy, not surgery, should immediately follow induction chemotherapy in potentially resectable patients to prevent tumor repopulation. The results of three phase II studies of docetaxel-based regimens as induction therapy of patients with locally advanced squamous cell carcinoma of the head and neck are reviewed and reported. Overall response rates ranged from 93% to 100%, with complete response rates of 40% to 63%. The primary toxicities were neutropenia and febrile neutropenia. A North American phase III trial, randomizing patients to docetaxel/cisplatin/fluorouracil or cisplatin/fluorouracil sequentially followed by chemoradiotherapy is being performed to determine whether docetaxel improves the complete response rate, organ preservation rate, and survival of patients treated with induction chemotherapy.

Semin Oncol 2000 Aug;27(4 Suppl 8):13-24

Steroid hormones induce HMG1 overexpression and sensitize breast cancer cells to cisplatin and carboplatin

Cisplatin is an anticancer drug that has enjoyed remarkable success against testicular tumors, but dose limiting side-effects have limited its application against a broader range of cancers. Previous studies have shown that high-mobility group (HMG) domain proteins such as HMG1 sensitize cells to cisplatin by shielding its major DNA adducts from nucleotide excision repair. Estrogen treatment increases HMG1 mRNA levels in breast cancer MCF-7 cells. Herein, we describe that treatment of human cancer cells having steroid hormone receptors with the appropriate hormone, estrogen and/or progesterone, significantly increases the potency of cisplatin and its analogue carboplatin by causing the overexpression of HMG1. These findings suggest that the proper combination of these drugs, which are already approved by the Food and Drug Administration, could have potential benefit in treating tumors such as ovarian or breast that carry the hormone receptors.

Proc Natl Acad Sci U S A 2000 May 23;97(11):5768-72

Methionine depletion enhances the antitumoral efficacy of cytotoxic agents in drug-resistant human tumor xenografts

Efficacy of chemotherapy is limited in numerous tumors by specific cellular mechanisms that inactivate cytotoxic antitumoral drugs, such as ATP-dependent drug efflux and/or drug detoxification by glutathione. In reducing ATP pools and/or glutathione synthesis, it might be possible to enhance the efficacy of drugs affected by such resistance mechanisms. Reduction of the ATP pool and glutathione content is achievable in cancer cells by depleting the exogenous methionine (Met) supply and ethionine. Thus, the rationale for the present study was to use Met depletion to decrease the ATP and glutathione pools so as to sensitize tumors refractory to cytotoxic anticancer drugs. Met depletion was achieved by feeding mice a methionine-free diet supplemented with homocysteine. The effects of Met depletion combined with ethionine and/or chemotherapeutic agents were studied using human solid cancers xenografted into nude mice. TC71-MA (a colon cancer) SCLC6 (a small cell lung cancer), and SNB19 (a glioma) were found to be refractory to cisplatin, doxorubicin, and carmustine, respectively. These three drugs are used to treat such tumors and are dependent for their activity on the lack of cellular ATP- or glutathione-dependent mechanisms of resistance. TC71-MA, SCLC6, and SNB19 were Met dependent because their proliferation in vitro and growth in vivo were reduced by Met depletion. Cisplatin was inactive in the treatment of TC71-MA colon cancer, whereas a methionine-free diet, alone or in combination with ethionine, prolonged the survival of mice by 2-fold and 2.8-fold, respectively. When all three approaches were combined, survival was prolonged by 3.3-fold. Doxorubicin did not affect the growth of SCLC6, a MDR1-MRP-expressing tumor. A Met-deprived diet and ethionine slightly decreased SCLC6 growth and, in combination with doxorubicin, an inhibition of 51% was obtained, with survival prolonged by 1.7-fold. Combined treatment produced greater tumor growth inhibition (74%) in SCLC6-Dox, a SCLC6 tumor pretreated with doxorubicin. Growth of SNB19 glioma was not inhibited by carmustine, but when it was combined with Met depletion, survival duration was prolonged by 2-fold, with a growth inhibition of 80%. These results indicate the potential of Met depletion to enhance the antitumoral effects of chemotherapeutic agents on drug-refractory tumors.

Clin Cancer Res 2000 Feb;6(2):643-53

Therapeutic effect of intralesional interferon (Roferon) in squamous cell carcinoma

Recombinant alpha-2 interferon (IFN)*Roferon*100,000 IU/ml was intralesionally administered in 8 cases of squamous cell carcinoma (SCC) three times a week during 4-6 weeks in inoculations of 1 ml each. The therapeutic effect was scored as major-more than 60% reduction of the tumor size, moderate*30-60% reduction of the tumor mass and, nonreactive*less than 30% reduction of the tumor size. Three cases showed a major reduction, three showed a moderate reduction and two patients showed no reduction of the tumor volume. Histopathological examination of the surgically removed tumors after completion of the Roferon administration confirmed the clinical diagnosis of squamous cell carcinoma and revealed that an intense leukocyte, mainly lymphocytes, infiltration can be observed along with necrotic centers, progressively surrounding and reducing in size the tumor islets, thus proving an intense activation of the immune effector reactions against tumor cells.

Rom J Intern Med 1992 Jul-Sep;30(3):207-10

Preliminary trial of nonrecombinant interferon alpha in recurrent squamous cell carcinoma of the head and neck

Fourteen patients with recurrent squamous cell carcinoma of the head and neck (SCCHN) were treated with 10 x 10(6) U of nonrecombinant interferon alpha (IFN) intramuscularly (IM) daily for 3 days every 28 days. There were 11 men and 3 women, with ages ranging from 48 to 74 years. Patients had previously been treated with surgery (9 patients), radiotherapy (13 patients), or chemotherapy (8 patients). All patients had measurable disease by physical exam and radiologic evaluation and a performance status of less than or equal to 2 (ECOG). Patients were treated for a minimum of 3 months and continued on therapy until disease progression. The dose and treatment schedule of IFN was well-tolerated. Toxicities included low-grade fever, mild anorexia, and malaise. Treatment was stopped in 1 patient due to the development of atrial fibrillation. One death occurred as a complication of aspiration pneumonia 2 weeks following the onset of therapy and was not felt to be related to IFN therapy. Of the 14 patients treated, there was 1 complete response (30+ months) of a base of tongue primary. Two patients had stabilization of disease (SD, 8 and 12 months). One patient had a mixed response with resolution of subcutaneous nodules. The remaining 10 patients died of progressive disease. Immunological assessment was performed on 8 patients. The 1 patient who had a complete response was noted to have markedly low pretreatment natural killer (NK) cell activity and a subsequent sharp rise in activity after initial treatment. We conclude that low-dose cyclic IFN is well-tolerated in patients with recurrent SCCHN and has potential antitumor activity.

Head Neck 1991 Jan-Feb;13(1):15-21

Interferon therapy for basal cell carcinoma and squamous cell carcinoma

Totally 161 basal cell and squamous cell carcinoma (BCC, SCC) patients were treated with human natural leucocytic interferon (HNLI) and recombinant IFN alpha 2c. After HNLI treatment, 61 out of 86 BCC patients and 29 out of 45 SCC patients were cured according to histopathologic and clinical findings. In 13 BCC and 13 SCC patients, the cancer lesion was reduced 25%-90%. After recombinant IFN alpha 2c treatment, 14 of 20 BCC patients and 4 of 10 SCC patients were cured according to histopathologic and clinical findings. In 6 BCC patients and 5 SCC patients the cancer lesion was reduced 25% to 90%. Both types of interferons are effective in the treatment of BCC and SCC patients. Local application of interferon stimulates immune reaction at the site of the tumor. There is a marked difference between the spontaneous macrophage activity and that induced by interferon. The interferon activated macrophages are significantly larger, the number of lysosomes and the density of macrophages is increased. In difficult locations intralesional therapy can be considered to avoid disfigurement of the patients with or without surgery.

Int J Clin Pharmacol Ther Toxicol 1991 Sep;29(9):342-6

Chronic myelocytic leukemia induced into remission by interferon-alpha associated with early esophageal cancer

A fifty-one-year-old male patient visited the Department of Dermatology of Toho University Ohashi Hospital with a complaint of generalized exanthema, which was diagnosed assyringoma; at that time his leukocytosis was recognized. He was admitted to our department on August 8, 1988. Physical examination on admission revealed slight hepatosplenomegaly. WBC count was elevated (50,700/microliters). He was diagnosed as having Ph1-positive CML in the chronic phase and was treated with IFN-alpha (HLBI, Sumitomo, 3 x 10(6) units/day, daily, I. M.) from August 12, but an elevated lesion was detected at the lower part of his esophagus by endoscopy, and it was diagnosed by biopsy as squamous cell carcinoma. Radical operation for esophageal cancer was performed on September 26; at that time his WBC count was 17,400/microliters. After discharge, his WBC level was maintained within normal range by IFN-alpha. On August 2, 1989, he was readmitted to our hospital because of lymphoblastic crisis. Although he attained transient complete remission, he died of pneumonia after the relapse on January 10, 1990. IFN-alpha therapy is suggested to be useful for the treatment of CML associated with gastrointestinal cancer because of its possible parenteral administration and mild toxicity.

Rinsho Ketsueki 1991 Jul;32(7):786-90

Expression of basic fibroblast growth factor protein and its down-regulation by interferons in head and neck cancer

BACKGROUND: Angiogenesis is crucial for tumor growth and metastasis. In several tumors, microvascular density has been shown to correlate with metastasis and aggressiveness. Basic fibroblast growth factor (bFGF) has potent angiogenic activity and has been identified in a wide variety of malignancies including head and neck squamous cell carcinomas (HNSCC). Material and Methods Frozen sections of 50 HNSCC were immunostained for von Willebrand factor and bFGF. Microvessels were counted by light microscopy; bFGF expression was studied at the light and electron microscopic level. Laryngeal cancer cell line HlaC79 was incubated with interferon (IFN) alpha and beta. bFGF quantification was performed by ELISA, and antiproliferative effects were determined by BrdU assay. RESULTS: The mean number of blood vessels (77.5 +/- 23.7) is significantly increased in HNSCC compared with controls (17.1 +/- 5.9). bFGF protein expression was detected in all HNSCC but not in control tissue. An correlation between bFGF expression and mean number of microvessels was found (p <.001). However, no correlation between bFGF expression and the main clinicopathologic features was shown. The long-term exposure (144 hr) of HNSCC cells to noncytostatic concentrations of IFN alpha and beta (>10 U/mL) down-regulated the protein production of bFGF. CONCLUSION: bFGF expression and angiogenesis are enhanced in HNSCC. The higher microvessel density in HNSCC with strong bFGF expression supports the importance of bFGF for tumor angiogenesis. IFN alpha and beta treatment leads to a down-regulation of bFGF expression independent of their antiproliferative effects, suggesting that IFN treatment might result in a reduction of angiogenesis in HNSCC.

Head Neck 2000 Mar;22(2):183-9

Effect of interferon-alpha (IFN alpha) on various human tumor xenografts

The growth of some human tumor xenografts (3 out of 8, melanoma, non-Hodgkin's lymphoma, squamous cell carcinoma) was successfully--but moderately and temporarily--inhibited, when interferon-alpha (EGIS, Hungary) was given for 10 days. The route of administration (intratumoral or intraperitoneal) was usually not a decisive factor. An attempt to potentiate IFNa action with Zymozan or Cyclophosphamide did not succeed.

Anticancer Res 1988 May-Jun;8(3):467-9

Gene amplification and overexpression of epidermal growth factor receptor in squamous cell carcinoma of the head and neck

The degree of gene amplification for epidermal growth factor receptor (EGFR) and its expression levels were examined in 4 cases of tumor lesions and their cell lines of human squamous cell carcinoma (SCC) of the oral cavity. The amplification was detected in 1 case (ZA), but not significantly in 3 other cases (HOC605, HOC815, and HOC927) in which the amplification did not occur during the cell line establishment. In those 3 cases, levels of EGFR synthesis and human EGF (hEGF) binding capacity were varied: HOC605 and HOC815 had slightly increased levels of hEGF binding capacity and EGFR synthesis, respectively. While HOC927 had the lowest levels of both, the hEGF binding capacity was elevated in the tumor lesion when compared with the normal counterpart of the same patient. These results suggest that the increased capacity for EGF binding plays a more important role than does gene amplification on the tumorigenesis of SCC of the head and neck.

Head Neck 1992 Jan-Feb;14(1):8-13

Characterization, quantification, and potential clinical value of the epidermal growth factor receptor in head and neck squamous cell carcinomas

Epidermal growth factor (EGF) stimulates the growth of several types of epithelial tissues and possesses a strong mitogenic activity that is mediated through its cell surface receptor (EGFR). The aim of this study was to characterize EGFR and measure its levels in head and neck tumors biopsies (70 patients); use of a simplified competition technique with a radiolabeled ligand allowed evaluation of functional EGFR. Five samples (4 tumors and 1 control) were used to characterize EGF binding. Graphic representation identified a single family of binding sites. Kd values revealed high affinity for EGF binding: mean Kd, 0.156 0.108 nM (0.095-0.347 nM). EGF-binding characteristics (Kd) were similar in nontumoral tissue samples (controls) and in tumor material. In 59 of 60 cases, EGFR levels were higher in the tumor than in the corresponding controls. A significant correlation was found between EGFR levels and tumor size and stage. Controls exhibited a trend toward higher EGFR levels in elevated sizes and stages. According to a cutoff EGFR value of 100 fmol/mg protein, which separated all controls from tumors, EGFR-positive tumors (greater than 100 fmol/mg protein) had a greater probability of complete response to chemotherapy than EGFR-negative tumors; other tumor characteristics, such as the degree of tumoral differentiation, tumor size, or stage, were unable to operate such a discrimination in the response to chemotherapy. EGFR may thus be an interesting biological marker for head and neck cancer.

Head Neck 1991 Mar-Apr;13(2):132-9

Epidermal growth factor receptor gene amplification and expression in head and neck cancer cell lines

We studied epidermal growth factor receptor (EGFR) gene amplification and expression in 11 early passage human head and neck carcinoma cell lines. Three cell lines demonstrated EGFR gene amplification and 10 lines showed an increase in EGFR mRNA when compared with normal keratinocytes, placenta, and a human skin carcinoma cell line. The effects of EGF on growth in 6 head and neck carcinoma cell lines was also studied. Growth inhibition at a concentration of 20 ng/mL was observed in one cell line but had no effect on growth in 5 cell lines. An increase in EGFR may be important in the etiology of, or progression of, head and neck carcinoma although the mechanisms need to be elucidated by further study.

Head Neck 1989 Sep-Oct;11(5):437-42

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