Strategies for Increasing the Efficacy of and Overcoming Resistance to Platinum Complexes In Vivo

  • Beverly A. Teicher
  • Sylvia A. Holden
  • Terence S. Herman
  • Emil FreiIII


Current anticancer drugs often cause solid tumor masses to regress but cure is usually not possible. In order to improve efficacy, we have tested a number of modulators of platinum complexes in an effort to use the altered physiology of tumor masses to advantage. Using the FSaIIC murine fibrosarcoma, tumor cell excision survival versus bone marrow CFUC survival rations were obtained for CDDP (10 mg/kg), carboplatin (100 mg/kg) and D,L-Tetraplatin (20 mg/kg) i.p. used in conjunction with Fluosol-DA/carbogen breathing for 6 hr., Etanidazole, Lonidamine, Pentoxifylline, Etoposide, SR-4233 or hyperthermia. Large improvements in the tumor cell kill to bone marrow CFU-GM kill ratios of 21–276 times were obtained with Fluosol-DA/carbogen and CDDP or Carboplatin, with etanidazole and CDDP or carboplatin and with local hyperthermia and CDDP. Lesser improvements were evident with the other combinations. By using the Hoechst 33342 dye assay we were able to improve the ratio of dim (putative hypoxic) versus bright (putative oxic) cell killing produced by CDDP with Fluosol-DA/carbogen, etanidazole, etoposide and SR-4233. Hyperthermia and radiation when added to CDDP resulted in relatively increased killing of bright cells. In the tumor growth delay assay additive or greater effects with CDDP were produced by Fluosol-DA/carbogen, etanidazole, lonidamine, SR-4233, hyperthermia and x-ray., while pentoxifylline, acetazolamide and etoposide probably produced less than additive increase in tumor growth delay with CDDP. These results indicate that by using modulators, platinum complex drugs can be made to be more selectively toxic toward tumor cells in general and physiologically selected tumor cell subpopulations in particular. This sort of approach may improve the clinical management of solid tumors.


Platinum Complex Tumor Growth Delay Therapeutic Ratio Local Hyperthermia Hypoxic Tumor Cell 
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. 1.
    B. A. Teicher, S. A. Holden, T. S. Herman, E. Alvarez Sotomayor, V. Khandekar, K. W. Rosbe, T. W. Brann, T. T. Korbut, and E. Frei, III, Characteristics of five human tumor cell lines and sublines resistant to cis-diamminedichloroplatinum(II). Int. J. Cancer. 47:in press (1991).Google Scholar
  2. 2.
    A. Basu, B. A. Teicher, and J. S. Lazo, Involvement of protein kinase C in cellular sensitivity to cis-diamminedichloroplatinum(II). J. Biol, Chem, 265:8451–8457 (1990).Google Scholar
  3. 3.
    P. Vaupel, S. Frinak, and H.I, Bicher, Heterogeneous oxygen partial pressure and pH distribution C3H mouse mammary adenocarcinoma, Cancer Res, 41:20089–2013 (1981).Google Scholar
  4. 4.
    P. Vaupel, H. P. Fortmeyer, S. Runkel, and F. Kallinowski, Blood flow, oxygen consumption and tissue oxygenation of human breast cancer xenografts in nude rats, Cancer Res. 47:3496–3503(1987).PubMedGoogle Scholar
  5. 5.
    C. W. Song, I. Lee, T. Hasegawa, J. G. Rhee, and S. H, Levitt, Increase in pO2 and radiosensitivity of tumors of Fluosol-DA (20%) and carbogen, Cancer Res, 47:442–446 (1987).PubMedGoogle Scholar
  6. 6.
    T. Hasegawa, J. G. Rhee, S. H. Levitt, and C. W. Song, Increase in tumor pO2 by perfluorochemicals and carbogen, Int. J. Radiat. Oncol. Biol. Phys. 13:569–574 (1987).PubMedCrossRefGoogle Scholar
  7. 7.
    K. A. Kennedy, B. A. Teicher, S. Rockwell, and A. C. Sartorelli, Chemotherapeutic approaches to cell populations of tumors, in: “Molecular Targets and Actions for Cancer Chemotherapeutic Agents,” A. C. Sartorelli, J. R. Bertino, and J. S. Lazo, ed., Academic Press, Inc., New York (1981).Google Scholar
  8. 8.
    P. M. Guillino, In vivo utilization of oxygen and glucose by neoplastic tissue, Adv. Exp. Med, Biol, 75:521–536 (1975).CrossRefGoogle Scholar
  9. 9.
    R. L. Momparler, In vitro systems for evaluation of combination chemotherapy, Pharmacol. Ther. Part A Chemother. Toxicol. Metab, Inhibitors, 8:21–35 (1980).Google Scholar
  10. 10.
    R Born, O. Hug, and K. R Trott, The effect of prolonged hypoxia on growth and viability of Chinese hamster ovary cells, Int. J. Radiat. Oncol. Biol, Phys, 1:687–697 (1976).CrossRefGoogle Scholar
  11. 11.
    L. H. Gray, A D. Conger, M. Ebert, S. Hornsey, and O. C. A. Scott, The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy, Br. J, Radiol, 26:638–648 (1953).CrossRefGoogle Scholar
  12. 12.
    A. C. Sartorelli, Therapeutic attack of hypoxic cells of solid tumors: Presidential address, Cancer Res. 48:775–778 (1988).PubMedGoogle Scholar
  13. 13.
    S. R Keyes, D. C. Heimbrook, P. M. Fracasso, S. Rockwell, S. G. Sligar, and A C. Sartorelli, Chemotherapeutic attack of hypoxic tumor cells by the bioreductive alkylating agent mitomycin C, Adv, Enzyme Regul, 23:291–307 (1985).CrossRefGoogle Scholar
  14. 14.
    K. A Kennedy, B. A Teicher, S. Rockwell, and A C. Sartorelli, The hypoxic tumor cell: a target for selective cancer chemotherapy, Biochem, Pharmacol, 29:1–8 (1980).CrossRefGoogle Scholar
  15. 15.
    B. A. Teicher, J. S. Lazo, and A. C., Sartorelli, Classification of antineoplastic agents by their selective toxicities toward oxygenated and hypoxic tumor cells, Cancer Res, 41:73–81 (1981).PubMedGoogle Scholar
  16. 16.
    B. A Teicher, T. S. Herman, S. A Holden, Y. Wang, M. R Pfeffer, J. M. Crawford, and E, Frei, III, Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo, Science, 247:1457–1461 (1990).PubMedCrossRefGoogle Scholar
  17. 17.
    L. Rice, M. Urano, H. D. Suit, The radiosensitivity of a murine fibrosarcoma as measured by three cell survival assays, Br. J, Cancer, 41:240–245 (1980).Google Scholar
  18. 18.
    B. A. Teicher, C.M, Rose, Perfluorochemical emulsion can increase tumor radiosensitivity, Science, 223:934–936 (1984).PubMedCrossRefGoogle Scholar
  19. 19.
    T. S. Herman, B. A Teicher, V. Chan, L. S. Collins, M. E. Kaufman, C. Loh, The effect of hyperthermia on the action of cis-diamminedichloroplatinum(II), (rhodamine-123)1[tetrachloroplati-num(II)], rhodamine-123 and potassium tetrachloroplatinate in vitro and in vivo, Cancer Res, 48:2335–2341 (1988).PubMedGoogle Scholar
  20. 20.
    C. Tsai, A F. Gazdar, D. J. Venzon, S. M. Steinberg, R L. Dedrick, J. L. Mulshine, B. S, Kramer, Lack of in vitro synergy between etoposide and cis-diamminedichloroplatinum(II), Cancer Res, 49:2390–2397 (1989).PubMedGoogle Scholar
  21. 21.
    D. J. Chaplin, P. L. Olive, R. E., Durand, Intermittent blood flow in a murine tumor: radiobiological effects, Cancer Res, 47:597–601 (1987).PubMedGoogle Scholar
  22. 22.
    P. L. Olive, D. J. Chaplin, R E. Durand, Pharmacokinetics, binding and distribution of Hoechst 33342 in spheroids and murine tumors, Br. J, Cancer, 52:739–746 (1985).CrossRefGoogle Scholar
  23. 23.
    T. A. Herman, B. A. Teicher, S. A. Holden, Trimodality therapy (drug/hyperthermia/radiation) with BCNU or mitomycin C, Int. J. Radiat. Oncol. Biol. Phys. 18:375–382(1990).PubMedCrossRefGoogle Scholar
  24. 24.
    T. S. Herman, B. A Teicher, S. A. Holden, L. S. Collins, Interaction of hyperthermia and radiation in murine cells: hypoxia and acidosis in vitro. tumor subpopulations in yjvQ, Cancer Res. 49:3338–3343(1989).PubMedGoogle Scholar
  25. 25.
    B. A. Teicher, T. S. Herman, S, A Holden, Combined modality therapy with bleomycin/hyperthermia/radiation, Cancer Res, 48:6291–6297 (1988).PubMedGoogle Scholar
  26. 26.
    B. A. Teicher, J. S. Lazo, and A. C., Sartorelli, Classification of antineoplastic agents by their selective toxicities toward oxygenated and hypoxic tumor cells, Cancer Res, 41:73–81 (1981).PubMedGoogle Scholar
  27. 27.
    B. A. Teicher, A. C. Sartorelli, Selective attachment of hypoxic tumor cells, in: “Design of Models for Screening of Therapeutic Agents for Cancer,” I. J. Fidler and R. K. White, ed., Van Nostrand, New York (1981).Google Scholar
  28. 28.
    T. S. Herman, B. A Teicher, S. A. Holden, M. R Pfeffer, and S. M, Jones, Addition of 2-nitromidazole radiosensitizers to trimodality therapy (cis-diamminedichloroplatinum II/hyperthermia/radiation) in the murine FSaIIC fibrosarcoma, Cancer Res, 50:2734–2740 (1990).PubMedGoogle Scholar
  29. 29.
    T. S. Herman, B. A Teicher, and C. N, Coleman, The interaction of SR-4233 with hyperthermia and radiation in the FSalIC murine fibrosarcoma tumor system in vitro and in vivo, Cancer Res, 50:5055–5059 (1990).PubMedGoogle Scholar
  30. 30.
    S. A Holden, G. Ara, T. S. Herman, C. N. Coleman, and B. A Teicher, SR-4233 as a chemosensitizer of antitumor alkylating agents (AA) in in vitro and in vivo. AACR abstract (1991).Google Scholar
  31. 31.
    B. A Teicher, S. A Holden, T. S. Herman, R Epelbaum, A B. Pardee, and B. Dezube, Effect of pentoxifylline as a modulator of alkylating agent activity in vitro and in vivo. Cancer Communications. in press (1991).Google Scholar
  32. 32.
    B. A. Teicher, T. S. Herman, S. A. Holden, R Epelbaum, S. Liu, and E. Frei, III, Lonidamine as a modulator of alkylating agent activity in vitro and in vivo. Cancer Res. in press (1991).Google Scholar
  33. 33.
    M. R Pfeffer, B. A. Teicher, S. A. Holden, A. Al-Achi, and T. S. Herman, The interaction of cisplatin plus etoposide with radiation ± hyperthermia, Int. J. Radiat. Oncol. Biol. Phys., 19:1439–1447(1991).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1991

Authors and Affiliations

  • Beverly A. Teicher
    • 1
  • Sylvia A. Holden
    • 1
  • Terence S. Herman
    • 1
  • Emil FreiIII
    • 1
  1. 1.Dana-Farber Cancer Institute and Joint Center for Radiation TherapyBostonUSA

Personalised recommendations