Summary
It is axiomatic that a given dose of an antitumor agent will not produce the same effect in 100% of the treated subjects. Numerous explanations regarding the sources of this heterogenenous response to drugs have been offered; however, there is a scarcity of experimental data allowing critical evaluation of the sources of variance. It is possible to study heterogeneous antitumor drug response in experimental, inbred animals. One animal model system, the advanced Ridgway osteogenic sarcoma, exhibits marked variation in its response to maximally tolerated doses of a number of clinically active antitumor agents. To evaluate the role of the host in the variable drug response, the tumor was bilaterally implanted into the flank regions of recipient AKR male mice. Treatment of the advanced tumor (200 mg–1,500 mg) with maximally tolerated doses of vincristine or l-phenylalanine mustard produced marked, but variable antitumor responses. Evaluation of a number of quantal and graded parameters of the chemotherapeutic response suggested that host heterogeneity contributes to variability. The host contribution was more apparent in this experimental model when the agent was noncurative. The underlying biological basis for the host heterogeneity is not known; however, it appears likely that pharmacological, immunological or other differences between the inbred animals account for the heterogeneity. Identification of these factors may be experimentally feasible in this animal model and help in the design of future studies in humans.
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References
Abe I, Sato S, Watanabe M, Sato H (1978) Mechanism of natural resistance of rat ascites hepatomas to 1-β-D-arabinofuranosylcytosine. Gan 69:557–564
Barranco SC, Drewinko B, Ho D, Humphrey RM, Romsdahl M (1972) Differential sensitivities of human melanoma cells grown in vitro to arabinosylcytosine. Cancer Res 32:2733–2736
Carpenter JT, Maddox WA, Laws HL, Wirtschafter DD, Soong SJ (1982) Favorable factors in the adjuvant therapy of breast cancer. Cancer 50:18–23
Erlichman C, Donehower RC, Chabner BA (1980) The practical benefits of pharmacokinetics in the use of antitumor agents. Cancer Chemother Pharmacol 4:139–145
Fidler IJ (1978) Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Res 38:2651–2660
Fidler IJ, Hart IR (1981) Biological and experimental consequences of the zonal composition of solid tumors. Cancer Res 41:3266–3267
Fisher B, Saffer EA (1981) Heterogeneity of tumor growth during chemoimmunotherapy: Observations in a murine model. In: Fidler IJ, White RJ (eds) Design of models for testing cancer therapeutic agents. Van Nostrand Reinhold, New York, pp 114–135
Geran RI, Greenberg NH, MacDonald MM, Schuhmacher AM, Abbott BJ (1972) Protocols for screening chemical agents and natural products against animal tumors and other biological systems, 3rd edn. Cancer Chemother Rep [3] 3:1–87
Griswold DP Jr, Schabel FM Jr, Wilcox WS, Simpson-Herren L, Skipper HE (1968) Success and failure in the treatment of solid tumors. I. Effect of cyclophosphamide on primary and metastatic plasmacytoma in the hamster. Cancer Chemother Rep 52:345–387
Hakansson L, Trope C (1974) On the presence within tumors of clones that differ in sensitivity to cytostatic drugs. Acta Pathol Microbiol Scand [A] 82:32–40
Heppner GH, Dexter DL, DeNucci T, Miller FR, Calabresi P (1978) Heterogeneity in drug sensitivity among tumor cell subpopulations of a single mammary tumor. Cancer Res 38:3758–3763
Kacser H, Burns JA (1973) In: Davies DD (ed) Rate control of biological processes, no 27. University Press, Cambridge, p 65
Mendiondo OA (1981) Multiple concurrent tumors in the same host: A model for chemotherapy. Cancer Immunol Immunother 10:257–259
Mendiondo OA, Suit HD, Sedlacek RS (1980) Concurrent and subsequent tumors in the same host: A model to evaluate the host tumor interaction. Int J Radiat Oncol Biol Phys 6:193–198
Nelson JA, Hokanson JA and Jenkins VJ (1982) Host factors in the variable chemotherapeutic response of advanced Ridgway osteogenic sarcoma. (Abstract) Proc Am Assoc Cancer Res 23:223
Salmon SE (1980) Cloning of human tumor stem cells. Alan R. Liss, New York
Schabel FM Jr (1975a) Animal models as predictive systems. In: Cancer chemotherapy: Fundamental concepts and recent advances. Year Book Medical Publishers, Chicago, pp 323–355
Schabel FM Jr (1975) In: Descriptions of systems used in experimental screening of anti-cancer preparations in sixteen countries (CAN/75/6), World Health Organization, Geneva, pp 80–82
Schabel FM Jr, Skipper HE, Trader MW, Laster WR Jr, Cheeks JB (1974) Combination chemotherapy for spontaneous AKR lymphoma. Cancer Chemother Rep 4:53–72
Schabel FM Jr, Griswold DP, Corbett TH, Laster WR Jr, Mayo JG, Lloyd HH (1979) Testing therapeutic hypotheses in mice and man: Observations on the therapeutic activity against advanced solid tumors of mice treated with anticancer drugs that have demonstrated or potential clinical utility for treatment of advanced solid tumors of man. In: Methods in Cancer Research Vol XVII Eds. H. Busch and V. Devita Jr. Academic Press Inc. NY pp. 3–50
Schabel FM Jr, Skipper HE, Trader MW, Laster WR Jr, Corbett TH, Griswold DP Jr (1980) Concepts for controlling drug-resistant tumor cells. In: Mouridsen HT, Palshof T (eds) Breast cancer. Experimental and clinical aspects. Pergamon Press, Oxford, pp 199–211
Schabel FM Jr, Griswold DP, Corbett TH, Laster WR Jr, Lloyd HH, Rose WC (1981a) Variable responses of advanced solid tumors of mice to treatment with anticancer drugs. In: Fidler IJ, While RJ (eds) Design of models for testing cancer therapeutic agents. Van Nostrand Reinhold, New York, pp 95–113
Schabel FM Jr, Griswold DP Jr, Corbett TH, Laster WR Jr (1981b) Increasing therapeutic response rates to anticancer drugs by applying the basic principles of pharmacology. Presented at: Cancer 1981/Cancer 2001 — An International Colloquium, sponsored by The University of Texas System Cancer Center, MD Anderson Hospital and Tumor Institute, Houston, Texas, Nov 11–14, 1981
Skipper HE (1964) Perspectives in cancer chemotherapy: Therapeutic design. Cancer Res 24:1295–1302
Skipper HE (1979) Ridgway osteogenic sarcoma: Response at different stages to surgery, single drugs, combinations of drugs and surgery chemotherapy. Universal-Microfilms International, Ann Arbor (Monograph publishing sponsor series)
Struck RF, Rose WC, Schabel FM Jr (1977) Attempts to develop a predicitive method for response of Ridgway osteogenic sarcoma to cyclophosphamide therapy. (Abstract) Proc Am Assoc Cancer Res 18:45
Suit HD, Sedlacek R, Wagner M, Orsi L, Silobrcic V, Rothman KJ (1976) Effect of Corynebacterium parvum on the response to irradiation of a C3H fibrosarcoma. Cancer Res 36:1305–1314
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Nelson, J.A., Hokanson, J.A. & Jenkins, V.K. Role of the host in the variable chemotherapeutic response of advanced Ridgway osteogenic sarcoma. Cancer Chemother. Pharmacol. 9, 148–155 (1982). https://doi.org/10.1007/BF00257743
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DOI: https://doi.org/10.1007/BF00257743