Effects of protein kinase and phosphatase inhibitors on the growth of human prostatic cancer cells

Konno S.; Cherry J.; Tazaki H.; Mallouh C.; Chiao J.W.
Dr. S. Konno, New York Medical College, Department of Urology, Valhalla, NY 10595 USA
Medical Science Research (United Kingdom), 1997, 25/5 (353-354)

The effects of protein kinase and phosphatase inhibitors on cell growth were investigated in human prostatic cancer, JCA-1, PC-3, and LNCaP cells. All four inhibitors showed a significant growth inhibitory effect, as determined by the (3H)thymidine incorporation method. The IC50 (50% inhibitory concentration) of each inhibitor was then calculated from the respective growth curves. Among the three cell lines, JCA-1 cells were relatively more susceptible to the inhibitors, while PC-3 cells were least sensitive. The IC50 data revealed that calphostin C and okadaic acid were more potent growth inhibitors than genistein and sodium orthovanadate. These results suggest that cell growth appears to be more effectively inhibited by the inhibitors of Ser/Thr-kinases/phosphatases (i.e. calphostin C and okadaic acid). Thus the family of Ser/Thr-kinases/phosphatases may be critically involved in regulating the growth of prostatic cancer cells.

Phyto-oestrogens and Western diseases

Adlercreutz H.; Mazur W.
Prof. H. Adlercreutz, Department of Clinical Chemistry, University of Helsinki, Meilahti Hospital, Haartmaninkatu 4, FIN-00290 Helsinki Finland
Annals of Medicine (United Kingdom), 1997, 29/2 (95-120)

Incidences of breast, colorectal and prostate cancer are high in the Western world compared to countries in Asia. We have postulated that the Western diet compared to the semivegetarian diet in some Asian countries may alter hormone production, metabolism or action at the cellular level by some biochemical mechanisms. Our interest has been focused on two groups of hormone-like diphenolic phyto-oestrogens of dietary origin, the lignans and isoflavonoids abundant in plasma of subjects living in areas with low cancer incidence. The precursors of the biologically active compounds detected in man are found in soybean products, whole-grain cereal food, seeds, and berries. The plant lignan and isoflavonoid glycosides are converted by intestinal bacteria to hormone-like compounds. The weakly oestrogenic diphenols formed influence sex-hormone production, metabolism and biological activity, intracellular enzymes, protein synthesis, growth factor action, malignant cell proliferation, differentiation, cell adhesion and angiogenesis in such a way as to make them strong candidates for a role as natural cancer-protective compounds. Their effect on some of the most important steroid biosynthetic enzymes may result in benes and action in the ce lls preventing development of cancer. Owing to their oestrogenic activity they reduce hot flushes and vaginal dryness in postmenopausal women and may to some degree inhibit osteoporosis, but alone they may be insufficient for complete protection. Soy intake prevents oxidation of the low-density lipoproteins in vitro when isolated from soy-treated individuals and affect favourably plasma lipid concentrations. Animal experiments provide evidence suggesting that both lignans and isoflavonoids may prevent the development of cancer as well as atherosclerosis. However, in some of these experiments it has not been possible to separate the phyto-oestrogen effect from the effect of other components in the food. The isoflavonoids and lignans may play a significant inhibitory role in cancer development particularly in the promotional phase of the disease, but recent evidence points also to a role in the initiation stage of carcinogenesis. At present, however, no definite recommendations can be made as to the dietary amounts needed for prevention of disease. This review deals with all the above-mentioned aspects of phyto-oestrogens.

Genistein inhibits proliferation and in vitro invasive potential of human prostatic cancer cell lines

Santibanez J.F.; Navarro A.; Martinez J.
Dr. J. Martinez, Unidad de Biologia Celular, INTA, Universidad de Chile, Casilla 138-11, Santiago Chile
Anticancer Research (Greece), 1997, 17/2 A (1199-1204)

Genistein -a natural flavone compound with antitumor activity- has been proposed as an effective agent to prevent the expression of metastasic capacity in hormone-dependent cancers. The present study represethe prolife ration and expression of the in vitro invasive capacity of tumoral prostatic cells with different invasive potential. In a cell culture system, genistein appeared to be cytotoxic and inhibitory of miaration through a Matriael barrier to PC-3 cells. the more aggressive invasive cell-line studied. DU-145 and LNCalphaP cells, which are less invasive than PC-3, are less affected by Genistein both with respect to proliferation rate and inhibition of u-PA and 72 kDa Gelatinase secretion. Measurement of the level of tyrosine-phosphoproteins in the three cell lines studied also showed that PC-3 cells are the most sensitive cells, with a possible molecular target in a membrane-bound protein of 130 kDa.

Soy and rye diets inhibit the development of Dunning R3327 prostatic adenocarcinoma in rats

Zhang J.-X.; Hallmans G.; Landstrom M.; Bergh A.; Damber J.-E.; Aman P.; Adlercreutz H.
Sweden
Cancer Letters (Ireland), 1997, 114/1-2 (313-314)

Two experiments were conducted to investigate the effect of soy and rye on the development of Dunning R3327 prostatic adenocarcinoma in rats.

Measurement and metabolism of isoflavonoids and lignans in the human male

Morton M.S.; Matos-Ferreira A.; Abranches-Monteiro L.; Correia R.; Blacklock N.; Chan P.S.F.; Cheng C.; Lloyd S.; Chieh-Ping W.; Griffiths K.
United Kingdom
Cancer Letters (Ireland), 1997, 114/1-2 (145-151):

Asian men, who consume a low fat/high fibre soya-based diet, have very much lower incidence of prostate cancer than men from North America and Europe. The soya bean is a rich source of the isoflavonic phyto-oestrogens, daidzein, genistein and equol, compounds which may be cancer-protective in Asian populations. The lignans, enterolactone and enterodiol, plant oestrogens derived from cereals and vegetables, may act in a similar manner in vegetarian men. We report here on the measurement of isoflavonoids and lignans, by gas chromatography-mass spectrometry, in prostatic fluid of men from Asia and Europe and also on the metabolism of these compounds in Western men following dietary supplementation.

Inhibition of N-methyl-N-nitrosourea-induced mammary tumors in rats by the soybean isoflavones

Constantinou A.I.; Mehta R.G.; Vaughan A.
Dr. A.I. Constantinou, University of Illinois, Department of Surgical Oncology, College of Medicine, 840 South Wood Street, Chicago, IL 60612 USA
Anticancer Research (Greece), 1996, 16/6 A (3293-3298)

Soy-based diets, rich in the isoflavones genistein and daidzein, are thought to protect against breast and prostate cancer. Soy-based diets, rich in the isoflavones genistein and daidzein, are thought to protect against breast and prostate cancer. We used the N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis animal model to test the effectiveness of these two isoflavones as chemopreventive agents. Each isoflavone was injected daily into 35-day-old rats for six months while we monitored the animals' body weight and mammary tumor appearance. Genistein was effective in reducing tumor multiplicity, but it reduced tumor incidence only marginally. Daidzein was less effective in reducing both tumor incidence and multiplicity. To investigate genistein's mechanism of action we determined the topoisomerase II (topo II) activity and detected the phosphotyrosine-containing peptides in the extracts of mammary tissues isolated from control and isoflavone-treated animals. tumors contained over 60-fold higher topo II enzymatic activity than the mammary glands. Similarly, more tyrosine phosphopeptides were detectable in mammary tumors than in mammary glands. Tissue samples from genistein treated animals contained similar topo II and protein tyrosine kinase (PTK) activities as the control group. These data suggest that mammary tumorigenesis is accompanied by an extensive increase in topo II and PTK activities. The mechanism of chemoprevention by genistein, however, is independent of topo II or PTK inhibition.

Genistein-induced apoptosis of prostate cancer cells is preceded by a specific decrease in focal adhesion kinase activity

Kyle E.; Neckers L.; Takimoto C.; Curt G.; Bergan R.
USA
Molecular Pharmacology (USA), 1997, 51/2 (193-200)

Genistein (5,7,4'-trihydroxyisoflavone), an isoflavinoid found in soy beans, has been identified as potentially causal for the low incidence of metastatic prostate cancer (PCa) in certain countries. Although genistein- induced PCa cell adhesion has been identified as a possible causative mechanism, direct growth inhibition by genistein has been reported and also could be causal. If in vivo growth inhibition was significant, then growth inhibition should occur at concentrations attained with dietary consumption, the mechanism of growth inhibition should be relevant to PCa, and genistein (a broad-spectrum in vitro protein-tyrosine kinase inhibitor) should have relatively specific kinase inhibitory effects in vivo. These considerations were investigated by measuring growth inhibitory activity in a variety of PCa cell lines. Growth inhibitory effects were shown not to occur with concentrations below the low micromolar range (i.e., 3 logs above that attained in serum). In-depth mechanistic studies with the PC3-M metastatic variant cell line demonstrated that growth inhibition was in was shown to decrease the viability of nonadherent cells, suggesting a lack of dependence on cell adhesion for growth inhibition. However, important molecular and kinetic differences between genistein's effects on growth in adherent versus nonadherent cells were identified. Specific suppression of focal adhesion kinase activity (without global decreases in phosphotyrosine) was shown to precede induction of apoptosis, which was responsible for growth inhibition in adherent cells. These findings do not support an in vivo growth inhibitory role by genistein consumed in quantities associated with a soy-based diet. They do, however, identify genistein as a potential therapeutic agent for PCa and as a tool with which to study the control of apoptosis in PCa.

Genistein-stimulated adherence of prostate cancer cells is associated with the binding of focal adhesion kinase to beta-1-integrin

Bergan R.; Kyle E.; Nguyen P.; Trepel J.; Ingui C.; Neckers L.
Clinical Pharmacology, Building 10, National Cancer Institute, NIH, Bethesda, MD 20892 USA
Clinical and Experimental Metastasis (United Kingdom), 1996, 14/4 (389-398)

The isoflavinoid genistein is a protein-tyrosine kinase inhibitor which has been identified as a putative cancer prevention agent. Its consumption is associated with a low incidence of clinical metastatic prostate cancer in the face of a sustained high incidence of organ-confined prostate cancer. We therefore undertook studies to examine genistein's effect upon cell adhesion as one possible mechanism by which it could be acting as an antimetastatic agent. A morphogenic analysis revealed that genistein caused cell flattening in a variety of cell lines: PC3-M, PC3, and DU-145 prostate carcinoma cells, as well as MCF-7 breast carcinoma cells. Mechanistic studies focused on the highly metastatic PC3-M cell line, and revealed that cell flattening was accompanied by an increase in cell adhesion. Further investigations demonstrated that focal adhesion kinase (FAK) accumulated in areas of focal cell attachment, and that this accumulation occurred only when cells were actively undergoing genistein-mediated morphologic change. Concurrent formation of a complex between the cell attachment molecule, beta-1-integrin, and FAK was shown to occur, and to correlate with transient activation of FAK activity. Genistein is presented as a novel investigative tool for use in the study of molecular events involved in the process of cell adhesion.

Quantification of genistein and genistin in soybeans and soybean products

Fukutake M.; Takahashi M.; Ishida K.; Kawamura H.; Sugimura T.; Wakabayashi K.
Biochemistry Division, Natl Cancer Ctr Research Institute, 1-1 Tsukiji, 5-chome, Chuo-ku, Tokyo 104 Japan
Food and Chemical Toxicology (United Kingdom), 1996, 34/5 (457-461)

It has been suggested that the isoflavone, may have some role as a chemopreventive agent against cancer in humans. Levels of genistein and its beta-glucoside conjugate, genistin, ingested in soybeans and related bean products by the Japanese were quantified by HPLC, to estimate daily intake of these compounds. Amounts of genistein and genistin in soybeans, soy nuts and soy powder were in the range of 4.6 to 18.2 and 200.6 to 968.1 microg/g food, respectively. The values for soy milk and tofu (bean curd) were 1.9 to 13.9 and 94.8 to 137.7 microg/g food, respectively. Levels of isoflavones in fermented soybean products, miso (bean paste) and natto (fermented soybeans), were 38.5 to 229.1 microg/food for genistein and 71.7 to 492.8 microg/g food for genistin. Thus, the level of genistein in the fermented soybean products was higher than in soy beans and soybean products such as soy milk and tofu. From these observations, it is suggested that the beta-glycosyl bond of genistin is cleaved to produce genistein by microbes during fermentation to yield mise and natto. Soy sauce was also found to contain both isoflavones, but at levels lower than in miso and natto. On the basiual consumption of soybeans and related products, daily intake of genistein and genistin by the Japanese is calculated to be 1.5-4.1 and 6.3-8.3 mg/person, respectively. These levels are much higher than those for Americans or Western Europeans, whose mortality rates for breast, colon and prostate cancers are greater than the Japanese.

Molecular effects of genistein on estrogen receptor mediated pathways

Wang T.T.Y.; Sathyamoorthy N.; Phang J.M.
Lab Nutritional Molecular Regulation, NCI-Frederick Cancer Res Dev Ctr, NIH, Frederick, MD 21702-1201 USA
Carcinogenesis (United Kingdom), 1996, 17/2 (271-275)

Genistein, a component of soy products, may play a role in the prevention of breast and prostate cancer. However, little is known about the molecular mechanisms involved. In the present study, we examined the effects of genistein on the estrogen receptor positive human breast cancer cell line MCF-7. We observed that genistein stimulated estrogen-responsive pS2 mRNA expression at concentrations as low as 10-8 M and these effects can be inhibited by tamoxifen. We also showed that genistein competed with (3H)estradiol binding to the estrogen receptor with 50% inhibition at 5 X 10-7 M. Thus, the estrogenic effect of genistein would appear to be a result of an interaction with the estrogen receptor. The effect of genistein on growth of MCF-7 cells was also examined. Genistein produced a concentration-dependent effect on the growth of MCF-7 cells. At lower concentrations (10-8-10-6 M) genistein stimulated growth, but at higher concentrations (>10-5 M) genistein inhibited growth. The effects of genistein on growth at lower concentrations appeared to be via the estrogen receptor pathway, while the effects at higher concentrations were independent of the estrogen receptor. We also found that genistein, though estrogenic, can interfere with the effects of estradiol. In addition, prolonged exposure to genistein resulted in a decrease in estrogen receptor mRNA level as well as a decreased response to stimulation by estradiol.

Effects of soya consumption for one month on steroid hormones in premenopausal women: Implications for breast cancer risk reduction

Lu L.-J.W.; Anderson K.E.; Grady J.J.; Nagamani M.
Preventive Med./Commun. Health Dept., 2.102 Ewing Hall, University of Texas Medical Branch, Galveston, TX 77555-1110 USA
Cancer Epidemiology Biomarkers and Prevention (USA), 1996, 5/1 (63-70)

Soybean consumption is associated with reduced rates of breast, prostate, and colon cancer, which is possibly related to the presence of isoflavones that are weakly estrogenic and anticarcinogenic. We examined the effects of soya consumption on circulating steroid hormones in six healthy females 22- 29 years of age. Starting within 6 days after the onset of menses, the subjects ingested a 12-oz portion of soymilk with each of three meals daily for 1 month on a metabolic unit. Daily isoflavone intakes were similar100 mg of daidzein (mostly as daidzin) and similar100 mg of genistein (mostly as genistin). Serum 17beta-estradiol levels on cycle days 5-7, 12-14, and 20-22 decreased by 31% (P = 0.09), 81% (P = 0.03), and 49% (P = 0.02), respectively, during soya feeding. Decreases persisted for two to three menstrual cycles after withdrawal from soya feeding. The luteal phase progesterone levels decreased by 35% during soya feeding (P = 0.002). Dehydroepiandrosterone sulfate levels decreased progressively during soya feeding by 14-30% (P = 0.03). Menstrual cycle length was 28.3 plus or minus 1.9 days before soymilk feeding, increased to 31.8 plus or minus 5.1 days during the month of soymilk feeding (P = 0.06), remained increased at 32.7 plus or minus 8.4 days (P = 0. 11) at one cycle after termination of soymilk feeding, and returned to pre-soya diet levels five to six cycles later. These results suggest that consumption of soya diets containing phytoestrogens may reduce circulating ovarian steroids and adrenal androgens and increase menstrual cycle length. Such effects may account at least in part for the decreased risk of breast cancer that has been associated with legume consumption.

Early di. An update

D'Amico A.; Motta L.; Ficarra V.; Pianon R.; Malossini G.; Tallarigo C.; Comunale L.; Mobilio G.
Italy
Medecine Biologie Environnement (Italy), 1996, 24/2 (139-152)

The main disagreements concerning the early diagnosis and the screening of prostate carcinoma are due to the lack of clinical evidence that the discovery of an early stage tumor, followed by a radical surgical treatment, does induce a prolonged survival of the patients and/or an improvement of the quality of life. However, many clinical studies on the epidemiology and the natural history of the disease suggested the efficacy of the early diagnosis. Moreover, the volume of neoplasia diagnosed by screening programs and surgically treated is generally higher than 0.5 ml and this is certainly an important clinical value. The dosage of serum PSA was particularly be reliable to detect an early diagnosis, according to its higher diagnostic accuracy if compared with digital rectal examination and transrectal ultrasonography. The combination of these diagnostic methods increased the accuracy of the whole clinical picture. In order to increase total PSA specificity by reducing its false positive values, especially when marker's values are only slightly augmented (ranged between 4.1 and 10 ng/ml), many approaches may be adopted, such as the evaluation of PSA velocity (PSAV), the assessment of PSA density (PSAD), the appropriate use of specific PSA values according to the different age of the patients and, especially, the comparison between free and complexed PSA dosages to total PSA values. In particular, it has been, recently observed that free PSA and total PSA ratio shows a more marked specificity than total PSA at the same degree of sensitivity. However, it is necessary to assess for international standard parameters concerning both total PSA and its molecular forms, since clinical observations were generally carried out through many different laboratory tools and according to different reference values. Finally, the research on prognostic factors which might foresee the developing power of the single tumor detected into the prostate, may provide useful information in order to select the patients who may benefit from a radical surgical treatment.

Prostate-specific antigen as a screening test for prostate cancer: The United States experience

Arcangeli C.G.; Ornstein D.K.; Keetch D.W.; Andriole G.L.
USA
Urologic Clinics of North America (USA), 1997, 24/2 (299-306)

Serum PSA-based early detection for prostate cancer has been studied fairly extensively for the past several years. It appears that we can state fairly categorically what the relative performances of total serum PSA, DRE, and TRUS are in detecting early-stage prostate cancer; that initial screening is effective in detecting histologically significant and pathologically organ-confined prostate cancer; that annual, serial, repetitive screening, at least over a 4- to 5-year horizon, does not overdetect prostate cancer, and that the results of early detection will improve as our ability to use certain PSA transformations such as PSA density, PSA slope, age-specific PSA adjustment, and knowledge of free versus total serum PSA is better characterized. These advances in our ability to diagnose early-stage prostate cancer likely will be coupled with an increased ability to predict the behavior, curability, and significance of individual tumors. It is hoped that information soon will be available to allow physicians to categorize an individual tumor as insignificant, significant and surgically curable, or significant and incurable by standard approaches. This ability, coupled with the demon strated ability to detect prostate cancer, will make an even more compelling argument for widespread PSA-based screening. At present, annual DRE and total serum PSA measurements are recommended for men older than 50 and among younger men at high risk for prostate cancer. All suspicious DRE findings should be evaluated with prostatic biopsy. Among younger men, PSA levels over 2.5 ng/mL should be considered worrisome and further evaluated. For men older than 65, serum PSA levels above 4 ng/mL should be considered abnormal and warrant biopsy. Men with persistent serum PSA elevation and a negative biopsy should undergo repeat biopsy at least once, and perhaps more often if PSA slope exceeds 0.75 per year, if density is greater than 0.10, or if f-PSA is less than 20%.

Prostate cancer screening: The controversy

Assaf G.J.
Lebanon
Revue Medicale Libanaise (Lebanon), 1996, 8/3 (152-154)

As of 1993, prostate cancer is the most common cancer among men in the USA and Canada, and the second leading cause of cancer deaths in males. In 1980, of patients in whom the diagnosis of prostate cancer was made clinically, 40% had disease beyond the prostate gland, for the most part an incurable condition. One should always bear in mind that localized prostate cancer is asymptomatic. The obstructive voiding symptoms rarely occur with localized organ confined prostate cancer. Few years ago, the PSA (prostate specific antigen) serologic test was developed, as a methodology for screening patients for prostate cancer, seeking the detection of this disease at an early stage. We will discuss the natural history of prostate cancer, early detection of this disease and the limitations of the PSA determination.

Clinical utility of measurements of free and total prostate-specific antigen (PSA): A review

Catalona W.J.
Division of Urologic Surgery, Washington Univ. Sch. of Medicine, 4960 Childrens' Place, St. Louis, MO 63110 USA
Prostate (USA), 1996, 29/SUPPL. 7 (64-69)

BACKGROUND. Prostate-specific antigen (PSA) is a widely-used tumor marker to aid in the early detection of prostate cancer. PSA testing has appreciable false-positive and false-negative results, particularly in the 2.5-10.0 ng/ml range. Measurements of the percentage of nonprotein-bound (free) PSA in serum, which is lower in patients with prostate cancer, has been evaluated as a method for increasing the accuracy of PSA testing.

METHODS. The literature on forms of PSA in serum, as it relates to issues of clinical utility for prostate cancer screening, was reviewed and summarized through May 1996.

RESULTS. Measurements of the percentage of free PSA in serum increases the accuracy of PSA testing for prostate cancer in men whose total PSA levels are 2.5-10.0 ng/ml. Cutoffs for screening are affected by prostate volume and total PSA levels. One study also demonstrated a correlation between percentage of free PSA and pathologic features of cancer aggressiveness.

CONCLUSIONS. Measurement of free PSA in serum has potential clinical utility for increasing the sensitivity and specificity of PSA screening. Insufficient data are available to establish cutoffs to be used in clinical practice. Cutoffs are affected by total PSA level and prostate volume. The prevalence rate of cancer in the screened population (age, race, previous biopsy history, etc.) will also influence screening cutoffs. Percentage of free PSA may also correlate with the potential aggressiveness of early-stage prostate cancer.

Detection of human papillomavirus DNA and p53 gene mutations in human prostate cancer

Suzuki H.; Komiya A.; Aida S.; Ito H.; Yatani R.; Shimazaki J.
Department of Urology, School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba-shi, Chiba 260 Japan
Prostate (USA), 1996, 28/5 (318-324)

The relationship between integration with human papillomavirus (HPV) and p53 gene mutations in tissues of prostate cancer was examined. Tissue samples analyzed were obtained by tofrom autopsy (22 endocrine therapy-resist ant metastatic disease cases). HPV DNA was detected in 8 of 51 (16%, 5 in stage B and 3 in autopsy cases) by polymerase chain reaction (PCR) using consensus primers on L1 region. Genotypes of HPV were entirely type 16. Structural abnormalities of p53 gene were detected in 7 of the 22 autopsy cases (32%) by PCR-single-strand conformation polymorphism analysis and direct sequencing. No p53 gene mutation was found in stage B cancer cases. Analysis of mutation spectra revealed clear differences between Japanese and Westerners. There was a significant difference in the mutation frequency between stage B and autopsy cases (P < 0.01, Fisher's exact test). One case showed both integration of HPV and p53 gene mutation in different cancer foci. However, the other cases revealed an inverse correlation between the presence of HPV DNA and p53 gene mutations. These data show that p53 genetic alteration is correlated with the progression of prostate cancer, in contrast to the integration of HPV that may occur in a relatively early stage. In conclusion, this study may indicate that either p53 gene mutation or the presence of HPV's oncogenic protein E6 is involved in the development of prostate cancer.

Effects of potent vitamin D3 analogs on clonal proliferation of human prostate cancer cell lines

De Vos S.; Holden S.; Heber D.; Elstner E.; Binderup L.; Uskokovic M.; Rude B.; Chen D.L.; Le J.; Cho S.K.; Koeffler H.P.
Dr. S. De Vos, Cedars-Sinai Medical Center, Davis Bldg. 5034, UCLA School of Medicine, 8700 Beverly Blvd., Los Angeles, CA 90048 USA
Prostate (USA), 1997, 31/2 (77-83)

BACKGROUND. Management of prostate cancer that has spread outside of the prostate capsule is a difficult problem. Innovative, non-toxic approaches to the disease are required. New, relatively non-toxic vitamin D3 analogs have recently been synthesized. We report that several of these compounds have marked antiproliferative effects on prostate cells.

METHODS. The clonal antiproliferative activity of five novel analogs of 1,25 dihydroxyvitamin D3 (1,25(OH)2D3, (cmpd C)) as well as 1,25(OH)2D3 itself was tested on three human prostate cancer cell lines (PC-3, LNCaP, and DU-145). The analogs were 20-epi-22oxa-24a,26a,27a-tri-homo- 1alpha,25(OH)2D3 (code name: KH 1060); 24a26a27a-tri-homo-22,24-diene- 1alpha,25(OH)2D3 (code name: EB 1089); 1,25(OH)2-16ene-D3 (code name: HM); 1,25(OH)2-16ene-23yne-D3 (code name: V); 1,25(OH)2-20-epi-D3 (code name: MC 1288)).

RESULTS. With the parent compound (1,25(OH)2D3), the effective dose that inhibited 50% clonogenic growth of PC-3 and LNCaP was 10-8M and 7 x 10-9 M, respectively. For these prostate cancer cell lines, KH 1060 was the most potent analog by an order of 25- to 35-fold as compared to cmpd C. The second and third most potent analogs were HM and MC 1288. DU-145 was resistant to all the vitamin D3 analogs. The major side-effect of 1,25(OH)2D3 is the production of hypercalcemia. The relative inhibitory index (RII) was determined by comparing the antiproliferative activity of the analog to its ability to produce hypercalcemia in mice injected intraperitoneally every other day. The KH 1060 had the best RTI: 50- to 70- fold greater than 1,25(OH)2D3 for PC-3 and LNCaP, respectively.

CONCLUSIONS. A trial of one or more of theatment of minimal residual disease of prostate cancer.

1,25-Dihydroxyvitamin D3 and 9-cis-retinoic acid act synergistically to inhibit the growthcause accumulation of cells in G1

Blutt S.E.; Allegretto E.A.; Pike J.W.; Weigel N.L.
USA
Endocrinology (USA), 1997, 138/4 (1491-1497)

Recent studies have suggested that the active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3, can inhibit the growth and/or induce the differentiation of a variety of cell types and that these characteristics might be useful in the treatment of some cancers. Retinoids also promote the differentiation and inhibit the growth of some cells. That the vitamin D receptor acts as a heterodimer with the retinoid X receptor (RXR) suggests that there may be functional interactions between 1,25-dihydroxyvitamin D3 and retinoids. In this study, we show that the combination of 1,25- dihydroxyvitamin D3 and 9-cis retinoic acid synergistically inhibits the growth of LNCaP prostate cancer cells. That this effect is mediated by RXR rather than retinoic acid receptors was shown using RXR- and retinoic acid receptor-specific ligands. The vitamin D3 analog, EB1089, inhibited growth more effectively than 1,25-dihydroxyvitamin D3 and also acted synergistically with 9-cis-retinoic acid. These treatments caused cells to accumulate in the G1 phase of the cell cycle, suggesting that 1,25- dihydroxyvitamin D3 can regulate one or more factors critical for the G1/S transition.

Vitamin D receptor content and transcriptional activity do not fully predict antiproliferative effects of vitamin D in human prostate cancer cell lines

Zhuang S.-H.; Schwartz G.G.; Cameron D.; Burnstein K.L.
USA
Molecular and Cellular Endocrinology (Ireland), 1997, 126/1 (83-90)

Prostate cancer cell lines exhibit variable growth suppression by the hormonal form molecular basis for this differential sensitivity to 1,25 D3, we compared growth response to 1,25 D3, vitamin D receptor (VDR) content and VDR transcriptional activity in four well-characterized human prostate cancer cell lines: LNCaP, DU145, PC-3 and ALVA-31. In PC-3 and DU145 cells, relative lack of growth inhibition by 1,25 D3 (< 10% inhibition) correlates with very low levels of VDR (9-15 fmol/mg protein) compared to classical vitamin D3 target tissues (similar 75-200 fmol/mg protein). Transfection of DU145 and PC-3 cells with a VDR cDNA expression vector is sufficient to establish growth sensitivity to 1,25 D3, suggesting that low VDR levels are responsible for the failure of these cell lines to respond to 1,25 D3. LNCaP cells are highly sensitive to growth inhibition by 1,25 D3 (similar 55% inhibition) and contain similar 2-3-fold more VDR (25 fmol/mg) than the relatively 1,25 D3-insensitive PC-3 and DU145 cell lines. However, ALVA-31 cells display less than 20% growth inhibition to 1,25 D3 although they contain the highest levels of VDR (45 fmol/mg) of the four cell lines. Thus, sensitivity to growth inhibition by 1,25 D3 does not correlate with VDR content in ALVA-31 and LNCaP cells. This lack of correlation between VDR density and growth responses to 1,25 D3 led us to investigate VDR-mediated gene transcription in these cell lines. We employed two different naturally-occurring vitamin D response elements (VDREs) linked to a reporter gene. Reporter gene activation by 1,25 D3 correlated well with VDR content in all four cell lines. Therefore, compared to LNCaP cells, decreased sensitivity of ALVA-31 to growth inhibition by 1,25 D3 is not due to a decrease in the general transcriptional activity of VDR. We conclude that growth inhibition by 1,25 D3 in prostate cancer cells requires VDR but that this response is modulated by non-receptor factors that are cell line-specific.

A preliminary report on the use of transfer factor for treating stage D3 hormone-unr metastatic prostate cancer

Pizza G.; De Vinci C.; Cuzzocrea D.; Menniti D.; Aiello E.; Maver P.; Corrado G.; Romagnoli P.; Dragoni E.; LoConte G.; Riolo U.; Palareti A.; Zucchelli P.; Fornarola V.; Viza D.
Dr. G. Pizza, Immunodiagnosis/Immunotherapy Unit, 1st Division of Urology, Sant'Orsola-Malpighi Hospital, Via P. Palagi 9, 40138 Bologna Italy
Biotherapy (Netherlands), 1996, 9/1-3 (123-132)

As conventional treatments are unsuccessful, the survival rate of stage D3 prostate cancer patients is poor. Reports have suggested the existence of humoral and cell-mediated immunity (CMI) against prostate cancer tumour-associated antigens (TAA). These observations prompted us to treat stage D3 prostate cancer patients with an in vitro produced transfer factor (TF) able to transfer, in vitro and in vivo, CMI against bladder and prostate TAA. Fifty patients entered this study and received one intramuscular injection of 2-5 units of specific TF monthly. Follow-up, ranging from 1 to 9 years, showed that complete remission was achieved in 2 patients, partial remission in 6, and no progression of metastatic disease in 14. The median survival was 126 weeks, higher than the survival rates reported in the literature for patients of the same stage.

The role of vitamin D in normal prostate growth and differentiation

Konety B.R.; Schwartz G.G.; Acierno J.S. Jr.; Becich M.J.; Getzenberg R.H.
University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213 USA
Cell Growth and Differentiation (USA), 1996, 7/11 (1563-1570)

Although increasing data indicate a role for vitamin D in prostate cancer, littlis hormone in the noncancerous prostate. We examined the effect of 1,25-dihydroxyvitamin D3 (1,25 D) on the growth of noncancerous rat prostates in vivo. Rats were castrated and treated with vehicle (controls), 1,25 D, testosterone, or a combination of both hormones for 2 weeks. Histological examination of the harvested prostates revealed that 1,25 D had a selective regressive effect on epithelial cells in treated rats compared to untreated castrated rats and to normal uncastrated rats. However, 1,25 D stimulated stromal growth in the prostate. The mean prostatic weight of the vitamin D-treated rats was twice that of the untreated rats (0.13 plus or minus SEM 0.005 g versus 0.06 plus or minus SEM 0.006 g). The histological differences were less marked in the testosterone-supplemented animals. A greater degree of cellular differentiation was observed in the rats treated with testosterone and vitamin D compared to rats that received testosterone supplementation alone. Studies of the nuclear matrix composition revealed differences between the testosterone-supplemented and the testosterone and 1,25 D-treated rat prostates. We conclude that in the absence of testosterone, 1,25 D may exert a growth-promoting effect on the prostatic stroma in vivo. In concert with testosterone, it may play an important role in the growth and differentiation of the normal rat prostate.

Effects of 1,25 dihydroxyvitamin D3 and its analogues on induction of apoptosis in breast cancer cells

James S.Y.; Mackay A.G.; Colston K.W.
Department of Clinical Biochemistry, St George's Hospital, Medical School, London SW17 ORE United Kingdom
Journal of Steroid Biochemistry and Molecular Biology (United Kingdom), 1996, 58/4 (395-401)

Vitamin D derivatives have been shown both to inhibit the proliferation of cultured breast cancer cells and totumours in vivo. We have investig ated the ability of several vitamin D analogues to promote the regression of experimental rat mammary tumours. Our results revealed that one vitamin D compound in particular, EB1089 (1(S),3(R)-dihydroxy-20(R)-5'-ethyl-5'-hydroxy-hepta- 1',3'(E)-dien- 1'-yl)-9,10-secopregna-5(Z),7(E), 10(19)-triene), was highly effective at inhibiting tumour progression, without causing a significant rise in serum calcium concentration. Tumour regression occurs when the rate of cell. death is greater than the rate of cell proliferation. Apoptosis (programmed or active cell death) is an active, energy-dependent process in which a distinct series of biochemical and molecular events leads to the death of cells by specific signals. We have examined effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and the synthetic vitamin D analogue EB1089 on indices of apoptosis in cultured human breast cancer cells. The effects of the vitamin D compounds on the expression of two oncoproteins which may regulate apoptosis, bcl-2 and p53 were examined by Western analysis. In MCF-7 cell cultures treated for six days with 1,25(OH)2D3 or EB1089 (1 x 10-8 M), bcl-2 protein was reduced in comparison to control levels, whereas p53 protein was increased. In addition, the p21 protein, whose gene WAF-1 is induced by wild type p53, was also increased by both vitamin D compounds. Using Northern analysis, it was observed that 24-h treatment of MCF-7 cells with 1 x 10-8 M 1,25(OH)2D3 or EB1089 resulted in an induction of TRPM-2 (clusterin) mRNA, a gene associated with onset of apoptosis in the involuting prostate. Fragmentation of genomic DNA is a characteristic feature of apoptosis. With the terminal deoxynucleotidyl transferase (TdT) assay, 3'-OH DNA breaks indicative of DNA fragmentation were detected histochemically in MCF-7 cells treated with 1 x 10-8 M 1,25(OH)2D3 or EB1089 for four days prior to fixation and TdT reaction. Further evidence of apoptosis was obtained following six days treatment of MCF-7 cell cultures with 5 x 10-8 M 1,25(OH)2D3 or EB1089, utilizing a cell death ELISA assay, which measures the presence of histone-associated oligonucleosome complexes generated from DNA fragmentation. Taken together our findings indicate that vitamin D derivatives may play a role in regulating the expression of genes and protein products implicated in apoptosis.

Vitamin D receptor expression is required for growth modulation by 1alpha,25-dihydroxyvitamin D3 in the human prostatic carcinoma cell line ALVA-31

Hedlund T.E.; Moffatt K.A.; Miller G.J.
Department of Pathology, Box B-216, Univ. of Colorado Hlth Sciences Ctr, 4200 East Ninth Ave., Denver, CO 80262 USA
Journal of Steroid Biochemistry and Molecular Biology (United Kingdom), 1996, 58/3 (277-288)

Epidemiological data suggest that vitamin D3, obtained from dietary sources and sunlight exposure, protects against mortality from prostate cancer (PC). In agreement with this, the most active vitamin D metabolite 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2 D3) regulates the growth and differentiation of several human PC cell lines. Both genomic and non-genomic signalling pathways for 1,25(OH)2 D3 have been reported, although the mechanism of action in PC cells has not been defined. We now provide data supporting an active role for the nuclear vitamin D receptor (VDe growth-inhibitory effects of 1,25(OH)2 D3 on these cells. In the VDR-rich cell line ALVA-31, the observed changes in growth by 1,25(OH)2 D3 are preceded by significant changes in VDR mRNA expression, In contrast, the cell line JCA-1, containing few VDRs, fails to show both early changes in VDR gene expression and later changes in growth with 1,25(OH)2 D3. To assess the role of the VDR more directly, transfection studies were pursued. ALVA-31 cells were stably transfected with an antisense VDR cDNA construct in an attempt to reduce VDR expression. Antisense mRNA expression among clones was associated with: (a) reduced or abolished sensitivity to the effects of 1,25(OH)2 D3 on growth; (b) decreased numbers of VDRs per cell, as measured by radiolabelled-ligand binding; and (c) a lack of induction of the VDR-regulated enzyme 24-hydroxylase in response to 1,25(OH)2 D3. From these studies we conclude that the antiproliferative effects of 1,25(OH)2 D3 require expression of the nuclear VDR in this system.

Induction of transforming growth factor-beta autocrine activity by all-trans-retinoic acid and 1alpha,25-dihydroxyvitamin D3 in NRP-152 rat prostatic epithelial cells

Danielpour D.
Laboratory of Chemoprevention, National Cancer Institute, Building 41, Bethesda, MD 20892 USA
Journal of Cellular Physiology (USA), 1996, 166/1 (231-239)

Retinoids and vitamin D analogues are known to inhibit the proliferation of a variety of cells in culture and prevent the formation of certain tumors in mammals. Although it is well established that these hormones control the transcription of many genes upon binding to and activating specific nuclear receptors, the mechanisms by which they prevent cancer are as yet poorly understood. In this study the role of the transforming growth factor-p (TGF-beta) growth inhibitors, in promoting the biological activities of all-trans-retinoic acid (RA) and 1alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3) was studied in NRP-152 cells, a nontumorigenic epithelial line derived from rat dorsal-lateral prostate. Inhibition of growth by nanomolar concentrations of RA was associated with an increase in both mRNA and protein for all three TGF-beta isoforms, with greater and much earlier increases for TGF-betas 2 and 3 (5.5 h) than for TGF-beta1 (24 h). A monoclonal antibody against TGF-beta and TGF-beta1 latency associated peptide (LAP), both of which neutralize all three TGF-beta isoforms, each block the ability of RA to inhibit growth of NRP-152 cells by >95%. Neutralization of growth inhibition by isoform-specific antibodies suggested that all three TGF-betas are involved in this effect. The ability of RA to upregulate fibronectin and thrombospondin expression in NRP-152 cells was also blocked by the monoclonal antibody. 1,25-(OH)2D3, which also induced TCF-betas 2 and 3 but not TGF-beta1, and their respective mRNAs, also induced fibronectin and thrombospondin through induction of TGF-beta. Thus, autocrine production of TGF-betas may be a significant part of the mechanisms by which RA and 1,25-(OH)2D3 promote cellular differentiation.

Biologically active acylglycerides from the berries of saw-palmetto (Serenoa repens)

Shimada H.; Tyler V.E.; McLaughlin J.L.
J.L. McLaughlin, DMCMP, Sch. of Pharmacy/Pharmacal Sciences, Purdue University, West Lafayette, IN 47907 USA
Journal of Natural Products (USA), 1997, 60/4 (417-418)

Brine shrimp lethality-directed fractionation of the 95% EtOH extract of the powdered, dried berries of Serenoa repens (Bart.) Small (saw-palmetto) (Palmae) led to the isolation of two monoacylglycerides, 1-monolaurin (1) and 1-monomyristin (2). Compounds 1 and 2 showed moderate biological activities in the brine shrimp lethality test and against renal (A-498) and pancreatic (PACA-2) human tumor cells; borderline cytotoxicity was exhibited against human prostatic (PC-3) cells. The fruits and extracts of saw-palmetto are taken orally as an herbal medicine to prevent prostatic hyperplasias.

Effects of the lipidosterolic extract of Serenoa repens (Permixon (R)) on human prostatic cell lines

Ravenna L.; Di Silverio F.; Russo M.A.; Salvatori L.; Morgante E.; Morrone S.; Cardillo M.R.; Russo A.; Frati L.; Gulino A.; Petrangeli E.
Istituto Tecnologie Biomediche, via G. B. Morgagni 30/E, 00161 Roma Italy
Prostate (USA), 1996, 29/4 (219-230)

BACKGROUND. Permixon (R) is a drug used in the treatment of benign prostatic hyperplasia. We studied its androgenic and antiandrogenic effects in the prostatic cell line LNCaP and PC3, respectively responsive and unresponsive to androgen stimulation.

METHODS. We performed FACScan analysis to investigate toxicity, 3H thymidine and 35S methionine incorporation to determine antiproliferative and metabolic effects, electron microscopy to study ultrastructural changes and cotransfection experiments to elucidate the role of wild type androgeor.

RESULTS. In LNCaP cell line, Permixon (R) induced a double proliferative/differentiative effect, not observed in PC3 cells. In PC3 cells cotransfected with wild-type androgen receptors and CAT reporter genes under the control of a androgen responsive element, the drug inhibited androgen-induced CAT transcription.

CONCLUSIONS. Our data indicate a role of the androgen receptor in mediating the effects of Permixon (R) in LNCaP cells. Cotransfection experiments in PC3 cells support a clear antiandrogenic action of the drug.

Comparison of in vitro effects of the pure antiandrogens OH-flutamide, casodex, and nilutamide on androgen-sensitive parameters

Simard J.; Singh S.M.; Labrie F.; Schellhammer P.F.; Candas B.
Canada
Urology (USA), 1997, 49/4 (580-589)

Objectives. A combination of flutamide (Eulexin) or nilutamide (Anandron) with a luteinizing hormone-releasing hormone (LHRH) agonist or orchiectomy is the only therapy demonstrated to prolong life in prostate cancer. Recently, the low 50-mg daily dose of Casodex, an analogue of the pure antiandrogen flutamide, was chosen for clinical studies on the basis that the compound was 5 to 10 times more potent than flutamide, as suggested by data obtained in the inappropriate intact rat model. The present study was designed to compare the in vitro antiandrogenic activity of OH-flutamide (OH- FLU), the active metabolite of flutamide, Casodex, and nilutamide.

Methods. The effect of the antiandrogens was tested on two androgen-sensitive parameters, namely proliferation of the SEM-107 clone of Shionogi mouse mammary tumor ceils and secretion of the GCDFP-15 (gross cystic disease fluid protein 15 kDa) in T-47D and ZR-75-1 human breast cancer cells.

Results. The twofold stimulation of Shionogi cell proliferation caused by a 10-day exposure to 1 nM testosterone was competitively reversed by incubation with OH-FLU, Casodex, or nilutamide, at the respective IC50 values of 72, 243, and 412 nM. Moreover, the marked increase in GCDFP-15 release induced by 1 nM testosterone was blocked by OH-FLU, Casodex, or nilutamide at respective IC50 values of 29, 180, and 87 nM in T-47D cells and at 35, 142, and 75 nM in ZR-75-1 cells. Similar data were detected in 4-androstenedione-induced Shionogi cell proliferation and in dihydrotestosterone-induced GCDFP-15 secretion in T-47D cells.

Conclusions. OH-FLU is 3.1 - to 7.8-fold more potent than Casodex, as measured on two in vitro androgen-sensitive parameters, in agreement with our recent in vivo data obtained in the model of castrated rats supplemented with 4-androstenedione implants, in which threefold greater potency of flutamide was observed. The present data, as well as other data from the literature, strongly indicate the need to choose a more appropriate dose of Casodex for the treatment of prostate cancerlexin/USA scheri ng plough; anadron/FRA roussel uclaf; ru 23908/FRA roussel uclaf; casodex

Casodex ^(R) (Bicalutamide): Overview of a new antiandrogen developed for the treatment of prostate cancer

Blackledge G.R.P.; Cockshott I.D.; Furr B.J.A.
Dr. G.R.P. Blackledge, Medical Affairs Department, Zeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield SK10 4TG United Kingdom
European Urology (Switzerland), 1997, 31/Suppl. 2 (30-39)

Casodex ^(R) (bicalutamide, Zeneca Ltd), has been developed for prostate cancer therapy. Its preclinical, pharmacokinetic, pharmacodynamic, clinical efficacy and tolerability data are described, Casodex is a potent and specific nonsteroidal antiandrogen. Clinical studies indicated that Casodex is orally bioavailable and well absorbed, with a plasma half-life of around 1 week. A Casodex dose of 50 mg daily decreased prostatic acid phosphatase comparable with castration. This dose was, therefore, evaluated initially as monotherapy and later as a component of maximal androgen blockade. Using prostate specific antigen as an end point, Casodex 150 mg daily was well-tolerated with demonstrable evidence of activity. Casodex 150 mg monotherapy was less effective than castration in terms of efficacy in patients with metastatic disease at entry. However, in patients non-metastatic at entry, Casodex 150 mg monotherapy appeared to be equivalent to castration in terms of time to death (data immature). Casodex was well-tolerated. In combination treatment, Casodex at 50 mg daily was at least as effective as 750 mg flutamide (Eulexin (R), Schering-Plough International) with respect to time to treatment failure, equivalent in terms of survival, and better tolerated with respect to diarrhoea. In conclusion, Casodex is a good option for the antiandrogen component of maximal androgen blockade.

Recommended dose of flutamide with LH-RH agonist therapy in patients with advanced prostate cancer

Akaza H.; Isaka S.; Usami M.; Kanetake H.; Kotake T.; Koiso K.; Aso Y.
H. Akaza, Department of Urology, Institute of Clinical Medicine, University of Tsukuba, 1-1 Tennodai, Tsukuba City, Ibaraki 305 Japan
International Journal of Urology (Japan), 1996, 3/6 (468-471)

Background: in a recent study by the Casodex Combination Study Group, USA, patients in a flutamide (750 mg/day) plus LH-RH agonist group showed a high treatment failure rate, mainly due to flutamide-induced diarrhea and hepatotoxicity. Our current study was conducted to determine the optimal dose of flutamide for use in this type of combination therapy.

Methods: In a randomized, multicenter study, 30 patients (hormone untreated; stage C or D) were divided into 2 groups: flutamide 250 mg (125 mg x 2; 14 patients) and flutamide 375 mg (125 mg x 3; 16 patients), and each dose combined with either goserelin acetate (3.6 mg every 4 weeks) or leuprolide acetate (3.75 mg every 4 weeks). Goserelin and leuprolide were administered to patients in a 1:1 ratio. Flutamide monotherapjapan in our previous phase II study. The endpoints of this pilot study were the objective response and adverse events during the 12-week treatment.

Results: The objective response rate was 83.3% in the flutamide 250 mg group and 85.7% in the flutamide 375 mg group according to the Japanese response criteria for prostate cancer. Elevated PSA levels fell to within the normal range in 83.3% of the patients in the former group and in 93.3% of the patients in the latter group. One patient administered 250 mg of flutamide experienced diarrhea, while the serum COT and/or GPT were elevated in 3 patients administered 250 mg of flutamide acid 4 patients administered 375 mg of flutamide.

Conclusions: Based on the findings of this pilot study of maximal androgen-depletion therapy for advanced prostate cancer, 375 mg/day of flutamide is recommended in combination with an CH-RH agonist. Assessment of the effects of our recommended regimen on longer term survival, quality of life and antiandrogen withdrawal syndrome of patients treated requires additional patients and time for follow-up.

Bicalutamide (Casodex^(TM)

Schellhammer P.
USA
Expert Opinion on Investigational Drugs (United Kingdom), 1996, 5/12 (1707-1722)

Bicalutamide (Casodex^(TM)) is a relatively new non-steroidal anti-androgen indicated for use in combination therapy with castration for the treatment of advanced prostate cancer. Developed from a series of non-steroidal compounds related to flutamide, bicalutamide is a potent, orally active, well tolerated anti-androgen with a half-life compatible with once-daily administration. In the clinical programme in prostatic cancer, patients were exposed to bicalutamide in doses ranging from 10 - 600 mg. Doses of 10 - 200 mg have been shown to have intrinsic activity in terms of producing subjective improvement and objective responses, and daily doses of up to 600 mg are currently being evaluated. Results of monotherapy studies reveal that 50 mg of bicalutamide is less effective than castration in patients with advanced disease; Phase III monotherapy studies are ongoing to compare 150 mg of bicalutamide with castration. In monotherapy studies, both 50 mg and 150 mg of bicalutamide have an advantage over castration in allowing patients to maintain libido and sexual potency. As combination therapy, 50 mg bicalutamide and a luteinising hormone-releasing hormone (LHRH) analogue is at least as effective as 750 mg of flutamide and an LHRH analogue and is better tolerated. The overall safety and tolerability profile of bicalutamide is indicative of a well tolerated therapy that has a relatively low incidence of treatment-related withdrawals. Because of its efficacy in combination with medical castration, its excellent safety profile, and its convenient once-daily oral formulation, bicalutamide represents a valid choice for anti-androgen therapy when used in combination with castration for patients with advanced prostate cancer.

U.S. Drug and biologic approvals in 1994-1995

Beary III J.F.; Duchaine C.M.; Rhein R.W. Jr.
Div. Regulatory/Scientific Affairs, Pharmaceutical Research, Manufacturers of America, 1100 Fifteenth Street NW, Washington, DC 20005 USA
Drug Development Research (USA), 1996, 37/4 (197-207)

Since the introduction of the Prescription Drug User Fee in 1992, the mean approval time for new drugs has decreased from 29.9 months (1992) to 19.2 months (1995). In 1994, 22 new drugs and 1 biological were approved. In 1995, 28 drugs and 2 biologicals were approved.

Cryosurgery of prostate cancer. Use of adjuvant hormonal therapy and temperature monitoring - A one year follow-up

Lee F.; Bahn D.K.; McHugh T.A.; Kumar A.A.; Badalament R.A.
Dr. F. Lee, Prostate Center, Crittenton Hospital, 1101 W University Drive, Rochester, MI 48307 USA
Anticancer Research (Greece), 1997, 17/3 A (1511-1515)

Objective: To determine the clinical outcomes at one year of Stages T2-T3 prostate cancer by cryosurgery utilizing pretreatment with total androgen ablation therapy and temperature monitoring to control the freez347 pat ients have had 356 cryosurgical procedures. 280 have reached one year post treatment. Of these, 131 had re-evalation with prostatic biopsy and serum PSA.

Methods: Transrectal ultrasound (TRUS) measurement of tumor size and biopsy of extraprostatic space was used to stage patients into two main groups: confined (66.6%) versus non-confined (19.3%). Radiation failures (14.1%) formed a separate group. Failure rates for the 131 men include all cancer diagnosed during the one year period following cryosurgery.

Results: The one year failure rate for the study group was 19.8% (26/131). For stages T2a, T2b C, T3 and radiation failures, the rates of positive biopsies were 13.9%, 12.9%, 33.3% and 35%, respectively. For those with local control of cancer (negative biopsy), 80% had prostate specific antigen (PSA) levels of < 0.5 ng/ml. The statistical variables for persistent cancer with prostate specific antigen > 0.5 ng/ml were: sensitivity of 66.7%, PPV of 16.7%, NPV of 98% and specificity of 83.7%. A statistically significant difference exists between stages T2 vs T3 and radiation failures (p = < 0.5). Major complications of rectal fistula and total incontinence for previously non-treated cancer versus radiation failures were 0.33% and 8.7% respectively, a 26 times greater risk.

Conclusion: Results of cryosurgery for all stages of prostate cancer at one year are encouraging, being 80% free of disease (biopsy and prostate specific antigen). The morbidity of the previously non-treated cancers from this procedure for us was minimal with high patient acceptance. For radiation failures a local control rate of 65% was achieved. However, early in our experience significant morbidity did occur and our enthusiasm for attempted salvage was initially tempered.

Continued on the next page...