Advertisement

Pharmaceutical Research

, Volume 15, Issue 11, pp 1760–1766 | Cite as

Antiproliferative and Cytotoxic Effects of Geldanamycin, Cytochalasin E, Suramin and Thiacetazone in Human Prostate Xenograft Tumor Histocultures

  • Yuebo Gan
  • Jessie L.-S. Au
  • Jie Lu
  • M. Guillaume Wientjes
Article

Abstract

Purpose. We have shown that the three human prostate xenograft tumors, i.e. the androgen-dependent CWR22 tumor, and the androgen-resistant CWR22R and CWR91 tumors, are comparable to patient tumors in their expression of prostate specific antigen, multidrug resistance p-glycoprotein, p53 and Bcl-2 and in their sensitivity to doxorubicin and paclitaxel. The present study used histocultures of these xenograft tumors to evaluate the antiproliferative and cytotoxic effects of several drugs (geldanamycin, cytochalasin E and thiacetazone), which have diverse action mechanisms and have shown activity against primary cultures of human prostate cancer cells. Suramin, a clinically active compound was included for comparison.

Methods. The antiproliferative effect of 96 h drug treatment was measured by inhibition of DNA precursor incorporation, and the cytotoxic or cell kill effect was measured by in situ DNA end labeling of apoptotic and necrotic cells and by reduction of live cell density.

Results. The rank order of molar potency was geldanamycin >cytochalasin E >suramin ≥ thiacetazone. Thiacetazone produced antiproliferation only in CWR22 tumor and had no cytotoxicity, whereas the other three drugs produced both antiproliferation and cytotoxicity in all three tumors. Geldanamycin, but not cytochalasin E and suramin, showed greater antiproliferation and cytotoxicity in tumor cells compared to normal stromal cells. The two androgen-resistant tumors were 4 to >40-fold less sensitive than the androgen-dependent tumor to drug-induced antiproliferation but were about equally or 4 to >20-fold more sensitive to drug-induced cytotoxicity. The ratios of drug concentrations that produced 50% antiproliferation to the concentrations that produced 50% cytotoxicity ranged from <0.04 to 0.3 in CWR22 tumor, but ranged from 0.3 to 2.7 in CWR22R and CWR91 tumors, indicating a shift from antiproliferation as the predominant drug effect in the androgen-dependent tumor to cytotoxicity in the androgen-resistant tumors.

Conclusions. Our results indicate (a) differential drug effects in human prostate xenograft tumors with antiproliferation and cytotoxicity as the predominant drug effect in the androgen-dependent and androgen-resistant tumors, respectively, (b) that progression of tumors from androgen-dependent state to androgen-resistant state appears to be associated with a lower sensitivity to drug-induced antiproliferation and an equal or greater sensitivity to drug-induced cytotoxicity, and (c) that geldanamycin but not thiacetazone warrants further development.

suramin geldanamycin cytochalasin E thiacetazone pharmacodynamics 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. 1.
    D. Peehl, E. Erickson, L. Malspeis, J. Orr, J. Mayo, R. Camalier, A. Monks, P. Cronise, K. Paul, and M. R. Greaver. Prostate cancer: NCI drug discovery efforts. Proc. Am. Assoc. Cancer Res. 34:369 (1993).Google Scholar
  2. 2.
    D. M. Peehl, E. Erickson, L. Malspeis, J. Mayo, R. F. Camalier, A. Monks, P. Cronise, K. Paull, and M. R. Grever. In vitro prostate cancer drug screen. In: Fundamental approaches to the diagnosis and treatment of prostatic cancer and BPH. K. Imai, J. Shimazaki, and J. P. Karr (eds). Adenine Press, Inc., New York, NY, pp. 203–207, 1994.Google Scholar
  3. 3.
    C. DeBoer, P. A. Meulman, R. J. Wnuk, and D. H. Peterson. Geldanamycin, a new antibiotic. J. Antibiot. (Tokyo) 33:442–447 (1970).Google Scholar
  4. 4.
    J. G. Supko, R. L. Hickman, M. R. Grever, and L. Malspeis. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother. Pharmacol. 36:305–315 (1995).Google Scholar
  5. 5.
    C. Chavany, E. G. Mimnaugh, P. Miller, R. Bitton, P. Nguyen, J. Trepel, L. Whitesell, R. Schnur, J. Moyer, and L. Neckers. p185(erb2) binds to GRP94 in vivo-dissociation of the p185(erb2)/GRP94 heterocomplex by benzoquinone ansamycins precedes depletion of p185(erb2). J. Biol. Chem. 271:4974–4977 (1994).Google Scholar
  6. 6.
    C. E. Stebbins, A. A. Russo, C. Schneider, N. Rosen, F. U. Hartl, and N. P. Pavletich. Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell 89:239–250 (1997).Google Scholar
  7. 7.
    L. Whitesell, E. G. Mimnaugh, B. De Costa, C. E. Myers, and L. M. Neckers. Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc. Natl. Acad. Sci. USA 91:8324–8328 (1994).Google Scholar
  8. 8.
    J. G. Cory, A. H. Cory, G. Rappa, A. Lorico, M. C. Liu, T. S. Lin, and A. C. Sartorelli. Inhibitors of ribonucleotides reductase. Comparative effects of amino-and hydroxy-substituted pyridine-2-carboxaldehyde thiosemicarbazones. Biochem. Pharmacol. 48:335–344 (1994).Google Scholar
  9. 9.
    M. Ligo, A. Hoshi, K. Kuretani, and M. Natsume. Antitumor activity of N-heterocyclic carboxaldehyde thiosemicarbazone derivatives. Gann 68:221–225 (1997).Google Scholar
  10. 10.
    M. Matsumoto, T. Tihan, and J. G. Cory. Effect of ribonucleotide reductase inhibitors on the growth of human colon carcinoma HT-29 cells in culture. Cancer Chemother. Pharmacol. 26:323–329 (1990).Google Scholar
  11. 11.
    S. S. Brown and J. A. Spudich. Cytochalasin inhibits the rate of elongation of actin filament fragments. J. Cell Biol. 83:657–662 (1979).Google Scholar
  12. 12.
    M. D. Flanagan and S. J. Lin. Cytochalasins block actin filament elongation by binding to high affinity sites associated with F-actin. J. Biol. Chem. 255:835–838 (1980).Google Scholar
  13. 13.
    C. E. Myers, R. V. La Rocca, M. R. Cooper, R. Danesi, C. A. Jamis-Dow, C. A. Stein, and W. M. Linehan. Role of suramin in cancer biology and treatment. In: S. Broder (ed). Molecular Foundations of Oncology. Baltimore: Williams & Wilkins, 1991, pp. 419–431.Google Scholar
  14. 14.
    T. G. Pretlow, C. M. Delmoro, G. G. Dilley, C. G. Spadafora, and T. P. Pretlow. Transplantation of human prostate carcinoma into nude mice in matrigel. Cancer Res. 51:3814–3817 (1991).Google Scholar
  15. 15.
    T. G. Pretlow, S. R. Wolman, M. A. Micale, R. J. Pelley, E. D. Kursh, M. I. Resnick, D. R. Bodner, J. W. Jacobberger, C. M. Delmoro, J. M. Giaconia, and T. P. Pretlow. Xenografts of primary human prostate carcinoma. J. Natl. Cancer Inst. 85:394–398 (1993).Google Scholar
  16. 16.
    M. A. Wainstein, F. He, D. Robinson, H. J. Kung, S. Schwartz, J. M. Giaconis, N. L. Edgehouse, T. P. Pretlow, D. R. Bodner, E. D. Kursh, M. I. Resnick, A. Seftel, and T. G. Pretlow. CWR22: Androgen-dependent xenograft model derived from a primary human prostatic carcinoma. Cancer Res. 54:6049–6052 (1994).Google Scholar
  17. 17.
    C. T. Chen, Y. Gan, J. L-S. Au, and M. G. Wientjes. Androgen-dependent and-independent human prostate xenograft tumors as models for drug activity evaluation. Cancer Res. 58:2777–2783 (1998).Google Scholar
  18. 18.
    S. R. Denmeade, X. S. Lin, and J. T. Isaacs. Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer. Prostate 28:251–265 (1996).Google Scholar
  19. 19.
    R. A. Vesico, C. H. Redfern, R. J. Nelson, S. Ugoretz, P. H. Stern, and R. M. Hoffman. In vivo-like drug responses of human tumors growing in three-dimensional gel-supported primary culture. Proc. Natl. Acad. Sci. USA 84:5029–5033 (1987).Google Scholar
  20. 20.
    G. R. Cunha, L. W. K. Chung, J. M. Shannon, O. Taguchi, and H. Fuji. Hormone-induced morphogenesis and growth: role of mesenchymal-epithelial interactions. Recent. Prog. Hormone Res. 39:594–598 (1983).Google Scholar
  21. 21.
    M. Tenniswood. Role of epithelial-stromal interactions in the control of gene expression in the prostate: a hypothesis. Prostate 9:375–385 (1986).Google Scholar
  22. 22.
    R. S. Kerbel, H. Kobayashi, and C. H. Graham. Intrinsic or acquired drug resistance and metastasis: are they linked phenotypes? J. Cell Biochem. 56:37–47 (1994).Google Scholar
  23. 23.
    W. C. Yen, T. S. Schmittgen, and J. L-S. Au. Differential pH dependency of mitomycin C activity in monolayer and 3-dimensional cultures. Pharm. Res. 13:1887–1891 (1996).Google Scholar
  24. 24.
    T. Furukawa, T. Kubota, and R. M. Hoffman. The clinical applications of the histoculture drug response assay. Clin. Cancer Res. 1:305–311 (1995).Google Scholar
  25. 25.
    T. Kubota, N. Sasano, O. Abe, I. Nakao, E. Kawamura, T. Saito, M. Endo, K. Kimura, D. Hiroshi, H. Sasano, H. Nagura, N. Ogawa, R. M. Hoffman, and the chemosensitivity study group for histoculture drug-response assay. Potential of the histoculture drug-response assay to contribute to cancer patient survival. Clin. Cancer Res. 1:1537–1543 (1995).Google Scholar
  26. 26.
    K. T. Robbins, K. M. Connors, A. M. Storniolo, C. Hanchett, and R. M. Hoffman. Sponge-gel-supported histoculture drug-response assay for head and neck cancer. Arch. Otolaryngol. Head Neck Surg. 120:288–292 (1994).Google Scholar
  27. 27.
    M. G. Wientjes, T. G. Pretlow, R. A. Badalament, J. K. Burgers, and J. L-S. Au. Histocultures of human prostate tissues for pharmacologic evaluation. J. Urol. 153:1299–1302 (1995).Google Scholar
  28. 28.
    Y. Gan, M. G. Wientjes, D. E. Schuller, J. L-S. Au. Pharmacodynamics of taxol in human head and neck tumors. Cancer Res. 56:2086–2093 (1996).Google Scholar
  29. 29.
    T. G. Pretlow, R. J. Pelley, and T. P. Pretlow. Biochemistry of prostatic carcinoma. In T. G. Pretlow and T. P. Pretlow (eds), Biochemical and molecular aspects of selected cancers. San Diego: Academic Press, 1994, pp. 169–237.Google Scholar
  30. 30.
    R. Nemoto, K. Uchida, T. Shimazui, K. Hattori, K. Koiso, and M. Harada. Immunocytochemical demonstration of S phase cells by anti-bromodeoxyuridine monoclonal antobody in human prostate adenocarcinoma. J. Urol. 141:337–340 (1989).Google Scholar
  31. 31.
    D. L. Scrivner, J. S. Meyer, N. Rujanavech, A. Fathman, and T. Scully. Cell kinetics by bromodeoxyuridine labeling and deoxyribonucleic acid ploid in prostate carcinoma needle biopsies. J. Urol. 146:1034–1039 (1991).Google Scholar
  32. 32.
    M. A. Eisenberger, V. J. Sinibaldi, L. M. Reyno, R. Sridhara, D. I. Jodrell, E. G. Zuhowski, K. H. Tkaczuk, M. Lowitt, R. K. Hemady, S. C. Jacobs, D. VanEcho, and M. J. Egorin. Phase I and clinical evaluation of a pharmacologically guided regimen of suramin in patients with hormone-refractory prostate cancer. J. Clin. Oncol. 13:2174–2186 (1995).Google Scholar
  33. 33.
    L. Whitesell, S. D. Shifrin, G. Schwab, and L. M. Neckers. Benzoquinonoid ansamycins possess selective tumoricidal activity unrelated to src kinase inhibition. Cancer Res. 52:1721–1728 (1992).Google Scholar

Copyright information

© Plenum Publishing Corporation 1998

Authors and Affiliations

  • Yuebo Gan
    • 1
    • 2
  • Jessie L.-S. Au
    • 1
    • 2
  • Jie Lu
    • 1
  • M. Guillaume Wientjes
    • 1
    • 2
  1. 1.College of PharmacyThe Ohio State UniversityColumbus
  2. 2.Comprehensive Cancer CenterThe Ohio State UniversityColumbus

Personalised recommendations