Development of Hormone Refractory Tumors: Adaption Versus Clonal Selection

  • H. Schulze
  • J. T. Isaacs
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 118)


One of the most common characteristics of cancers is their ability to develop resistance to chemotherapy and/or hormonal manipulation to which they were initially responsive (Skipper et al. 1978; Goldie and Coldman 1979, Isaacs 1982b; Ling 1982). For example, there is an initial response rate of prostatic cancer patients to androgen ablation of about 70%–80%. However, essentially all of these patients eventually relapse to an androgen-independent state in which further antiandrogen therapy is no longer effective. Following relapse, all further attempts to ablate the low level of non-testicular androgens remaining following castration, estrogen or luteinzing hormone releasing hormone (LH-RH) analogue therapy by means of hypophysectomy, adrenalectomy, or administration of direct-acting antiandrogens have proven unsuccessful in stopping the continuous tumor growth in this androgen-independent state (Scott et al. 1980; Schulze et al. 1987).


Prostatic Cancer Adrenal Androgen Cyproterone Acetate Androgen Ablation Androgen Ablation Therapy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Byar DP, Mostofi FK (1972) Carcinoma of the prostate: prognostic evaluation of certain pathological features in 208 radical prostatectomies, examined by the step section technique. Cancer 30: 5–13PubMedCrossRefGoogle Scholar
  2. Crawford ED, MeLeod D, Dorr A, Spaulding J, Benson R, Eisenberger M, Blumenstein B (1988) Treatment of newly diagnosed stage D2 prostate cancer with leuprolide and flutamide or leuprolide alone, phase III, intergroup study 0036. J Urol 139: 339AGoogle Scholar
  3. Devesa SS, Silverman DT (1978) Cancer incidence and morbidity trends in the United States: 1935–1974. J. Natl Cancer Inst. 60: 545–571PubMedGoogle Scholar
  4. Dunning WF (1963) Prostate cancer in the rat. NCI Monogr 12: 351–369Google Scholar
  5. Durham, SK, Dietze, AE (1986) Prostatic adenocarcinoma with and without metastasis to bone in dogs. J Am Vet Assoc 12: 1432–1436Google Scholar
  6. Giuliani L, Pescatore D, Giberti C, Martorana G, Natta G (1980) Treatment of advanced prostatic carcinoma with cyproterone acetate and orchiectomy. 5 year follow-up. Eur Urol 6: 145–148PubMedGoogle Scholar
  7. Goldie GH, Coldman AJ (1979) A mathematical model formulating the drug sensitivity of tumors to their spontaneous metastatic rate. Cancer Treat Rep 63: 1727PubMedGoogle Scholar
  8. Hakansson L, Troupe C (1974) On the presence within tumors of clones that differ in sensitivity to cytostatic drugs. Acta Pathol. Microbiol. Scand (A) 82: 32Google Scholar
  9. Hayashi T, Taki Y, Ikai K, Hiura M, Kiriyama T, Shizuki K (1987) Latent and clinically manifest prostatic carcinoma. Prostate 10: 275–279PubMedCrossRefGoogle Scholar
  10. Isaacs JT (1982a) Hormonally responsive versus unresponsive progression of prostatic cancer to antiandrogen therapy as studied with the Dunning R-3327—AT and -G rat adenocarcinomas. Cancer Res 42: 5010–5014PubMedGoogle Scholar
  11. Isaacs JT (1982b) Cellular factors in the development of resistance to hormonal therapy. In: Bruchovsky N, Goldie JH (eds) Drug and hormone resistance in neoplasia, vol I. CRC, Boca Raton, pp 139–156Google Scholar
  12. Isaacs JT (1984) The timing of androgen ablation therapy and/or chemotherapy in the treatment of prostatic cancer. Prostate 5: 1–18PubMedCrossRefGoogle Scholar
  13. Isaacs JT (1987) Control of cell proliferation and cell death in the normal and neoplastic prostate: a stem cell model. In: Rodgers CH, Coffey DS, Cunha G, Grayhack JT, Hinman F, Forton R (eds) benign prostatic hyperplasia, vol 2. NIH publication 87–2881. NIH, Bethesda, pp 85–94Google Scholar
  14. Isaacs JT, Coffey DS (1984) Adaptation vs. selection as the mechanism responsible for the relapse of prostatic cancer to androgen ablation as studied in the Dunning R-3327 —H adenocarcinoma. Cancer Res 41: 5070–5075Google Scholar
  15. Isaacs JT, Heston, WDW, Weissman, RM Coffey, DS (1978) Animal models of the hormon-sensitive and -insensitive prostatic adenocarcinomas: Dunning R-3327-H, R3327-HI, and $-3327-AT. Cancer Res 38: 4353–4359PubMedGoogle Scholar
  16. Isaacs JT, Wake N, Coffey DS, Sandberg AA (1982) Genetic instability coupled to clonal selection as a mechanism for tumor progression in the Duning R 3327 rat prostatic adenocarcinoma system. Cancer Res 42: 2353–2361PubMedGoogle Scholar
  17. Isaacs, JT, Isaacs WB, Feitz WFJ Scheres J. (1986) Establishment and characterization of seven Dunning rat prostatic cancer cell lines and their use in delveloping methods for predicting metastatic abilities of prostatic cancers. Prostate 9: 261–281.PubMedCrossRefGoogle Scholar
  18. Jesik CJ, Holland JM, Lee C (1982) An anatomic and histologic study of the rat prostate. Prostate 3: 81–97PubMedCrossRefGoogle Scholar
  19. Kastendieck H (1980) Correlation between atypical primary hyperplasia and carcinoma of the prostate. Histologic studies on 180 total prostatectomies due to manifest carcinoma. Path Res Pract 169: 366–387PubMedCrossRefGoogle Scholar
  20. Labrie F, Dupont A, Belanger A (1985) Complete androgen blockade for the treatment of prostate cancer. In: Devita VT Hellman S, Rosenberg S (eds) Important advances in oncology. Lippincott, Philadelphia, pp 193–217Google Scholar
  21. Labrie F, Dupont A, Belanger A, Emond J, Monfette G (1987) Flutamide in combination with castration (surgical or medical) is the standard treatment in advanced prostate cancer. J Drug Dev 1 (suppl 1)34–51Google Scholar
  22. Lepor H, Ross A, Walsh PC (1982) The influence of hormonal therapy on survival of men with advanced prostatic cancer- J Urol 128: 335–340PubMedGoogle Scholar
  23. Lesser B, Bruchovsky N (1973) The effects of testosterone, 5a-dihydrotestosterone, and adenosine 3’, 5’-monophosphate on cell proliferation and differentiation in rat prostate. Biochim. Biophys. Acta 308: 426–437PubMedGoogle Scholar
  24. Leuprolide Study Group (1984) Leuprolide versus diethylstilbestrol for metastatic prostatic cancer. N Engl J Med 311: 1281–1286CrossRefGoogle Scholar
  25. Ling V (1982) Genetic basis of drug resistance in mammalian cells. In: Bruchovsky N, Goldie JH (eds) Drug and hormone resistance in neoplasia, vol I. CRC, Boca Raton, pp 1–19Google Scholar
  26. McNeal JE (1983) Monographs in urology. In: Stamey TA (ed) Custom Princeton, vol 4, pp 3–33Google Scholar
  27. Menon M, Walsh PC (1979) Hormonal therapy for prostatic cancer. In: Murphy GP (ed) Prostatic cancer. PSG, Littleton,MA, pp 175–200Google Scholar
  28. Mostofi FK, Sesterhenn J (1981) The role of prostatic acid phosphatase in histological diagnosis of carcinoma of the prostate. Proceedings of the seventy-sixth annual meeting of the American Urological Association, Boston, Abstract 42Google Scholar
  29. Oesterling JE, Epstein JI, Walsh PC (1986) The inability of adrenal androgens of stimulate the adult human prostate: an autopsy evaluation of men with hypogonadotropic hypogonadism and panhypopituitarism. J Urol 136: 1030–1034PubMedGoogle Scholar
  30. Pollard M (1980) The Pollard tumors. In: Murphy GP (ed) Models for Prostate cancer. Liss, New York, pp 293–302Google Scholar
  31. Prout GR, Leiman B, Daly JJ, MacLoughlin RA, Griffin PP, Young HH (1976) Endocrine changes after diethylstilbestrol therapy. Urology 7: 148–155PubMedCrossRefGoogle Scholar
  32. Rivenson A, Silverman J (1979) The prostatic carcinoma in laboratory animals. Invest Urol 16: 468–478PubMedGoogle Scholar
  33. Sandford NL, Searle JW, Kerr JFR (1984) Successive waves of apoptosis in the rat prostate after regulated withdrawal of testosterone stimulation. Pathlogy 16: 406–410Google Scholar
  34. Schroeder FH, Klijn JG, de Jong FH (1987) Metastatic cancer of the prostate managed with buserelin versus buserelin plus cyproterone acetate. J Urol 137: 912–918PubMedGoogle Scholar
  35. Schulze H, Isaacs, JT, Coffey DS (1987) A critical review of the concept of total androgen ablation in the treatment of prostate cancer. In: Murphy GP et al. (eds) Prostate cancer. Part A. Prog Clin Biol Res 243: 1–19Google Scholar
  36. Schulze H, Kaldenhoff H, Senge T, Westfälische Prostata-Karzinom study group (1988) Evaluation of total versus partial androgen blockade in the treatment of advanced protatic cancer. Urol Int 43: 193–1PubMedCrossRefGoogle Scholar
  37. Scott, WW, Menon M Walsh PC (1980) Hormonal therapy of prostatic cancer. Cancer 45: 1929–1936PubMedGoogle Scholar
  38. Shain SA, McCullough B, Segaloff A (1975) Spontaneous adenocarcinoma of the ventral prostate of the aged AXC rats. J Natl Cancer Inst 55: 177–180PubMedGoogle Scholar
  39. Shain SA, McCullough B, Nitchuk M, Boesel RW (1977) Prostatic carcinogenesis in the AXC rat. Oncology 34: 114PubMedCrossRefGoogle Scholar
  40. Sinha AA, Blackard, CE, Seal USA (1977) A critical analysis of tumor morphology and hormone treatments in the untreated and estrogen-treated responsive and refractory human prostatic carcinoma. Cancer 40: 2836–2850PubMedCrossRefGoogle Scholar
  41. Skipper HE, Schabel FM, Lloyd MM (1978) Selection and overgrowth of specifically and permanently drug-resistant tumor cells. Exp Ther Kinetics 15: 207–217Google Scholar
  42. Smolev JK, Heston WD, Scott WW, Coffey DS (1977) Characterization of the Dunning R-3327—H prostatic adenocarcinoma. An appropriate animal model for prostatic cancer. Cancer Treat Rep 61: 273–287PubMedGoogle Scholar
  43. Thompson JB, Greenberg E, Pazianos A, Pearson OH (1974) Hypophysectomy in metastatic prostate cancer. NY State J Med 74: 1006–1008Google Scholar
  44. Viola MV, Fromowitz F, Oravez MS, Deb S., Finket G, Lundy J, Harel P, Thor A, Schlom J (1986) Expression of ras oncogene p21 in prostatic cancer. Engl. J Med 314: 133–137CrossRefGoogle Scholar
  45. Voigt W, Dunning WF (1974) In vivo metabolism of testosterone-3H in R-3327, an androgen—sensitive rat prostatic adenocarcinoma. Cancer Res 34: 1447–1450PubMedGoogle Scholar
  46. Voigt W, Feldman, M, Dunning WF (1975) 5a-Dihydrotestosterone binding proteins and androgen sensitivity in prostatic cancers of copenhagen rats. Cancer Res 35: 1840–1846Google Scholar
  47. Wake N, Isaacs JT, Sandberg AA (1982) Chromosomal changes associated with progression of the Dunning R-3327 rat prostatic adenocarcinoma system. Cancer Res 42: 4131–4142PubMedGoogle Scholar
  48. Ward JM, Reznik G, Stinson SF, Lattatuda CP, Longfellow DG, Cameron TP (1980) Histogenesis and morphology of naturally occuring prostatic carcinoma in the ACI/segHapBR rat. Lab Invest 43: 517–522PubMedGoogle Scholar
  49. Ware JL (1987) Prostate tumor progression and metastasis. Biochim. Biophys. Acta 907: 279–298PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin·Heidelberg 1990

Authors and Affiliations

  • H. Schulze
    • 1
  • J. T. Isaacs
    • 2
  1. 1.Urologische AbteilungMarienhospital, Universität BochumHerneGermany
  2. 2.Department of UrologyThe Johns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations