Abstract
Historically, many new anticancer agents were first detected in a prescreen; usually consisting of a molecular/biochemical target or a cellular cytotoxicity assay. The agent then progressed to in vivo evaluation against transplanted human or mouse tumors. If the investigator had a large drug supply and ample resources, multiple tests were possible, with variations in tumor models, tumor and drug routes, dose-decrements, dose-schedules, number of groups, etc. However, in most large programs involving several hundred in vivo tests yearly, resource limitations and drug supply limitations have usually dictated a single trial. Under such restrictive conditions, we have implemented a flexible in vivo testing protocol. With this strategy, the tumor model is dictated by in vitro cellular sensitivity; drug route by water solubility (with water soluble agents injected intravenously); dosage decrement by drug supply, dose-schedule by toxicities encountered, etc. In this flexible design, many treatment parameters can be changed during the course of treatment (e.g., dose and schedule). The discovery of two active agents are presented (Cryptophycin-1, and Thioxanthone BCN 183577). Both were discovered by the intravenous route of administration. Both would have been missed if they were tested intraperitoneally, the usual drug route used in discovery protocols. It is also likely that they would have been missed with an easy to execute fixed protocol design, even if injected IV.
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Corbett TH, Valeriote FA, Polin L, et al: Discovery of solid tumor active agents using a soft-agar-colony-formation disk-diffusion-assay. Cytotoxic Anticancer Drugs: Models and concepts for drug discovery and development, FA Valeriote, TH Corbett and LH Baker (eds), Kluwer Academic Publishers, p 33–87, Boston/Dordrecht, London, 1992.
Corbett T, Valeriote F, LoRusso P, et al: Tumor models and the discovery and secondary evaluation of solid tumor active agents. Int J Pharmacogn, Supp 33: 102–122, 1995.
Corbett T, Valeriote F, Baker L: Is the P388 murine tumor no longer adequate as a drug discovery model: Invest New Drugs 5: 3–20, 1987.
Corbett TH, Valeriote FA: Rodent Models in Experimental Chemotherapy, The Use of Rodent Tumors in Experimental Cancer Therapy: Conclusions and Recommendations, RF Kallman (ed), Pergamon Press, Chapt 50, pp 233–247, 1987.
Corbett T, Valeriote F, LoRusso P, et al: Use of rodent solid tumors for drug discovery. In: Cancer Drug Discovery, Chapter 5, BA Teicher (ed), Humana Press Inc, 1997.
Corbett TH, Griswold Jr DP, Roberts BJ, Peckham JC, Schabel Jr FM: Tumor induction relationships in development of transplantable cancers of the colon in mice of chemotherapy assays, with a note on carcinogen structure. Cancer Res 35: 2434–2439, 1975.
Corbett TH, Griswold Jr DP, Roberts BJ, Peckham JC, Schabel Jr FM: Evaluation of single agents and combinations of chemotherapeutic agents in mouse colon carcinomas. Cancer 40(5): 2660–2690, 1977.
Corbett TH, Roberts BJ, Leopold WR, Peckham JC, Wilkoff LJ, Griswold Jr DP, Schabel Jr FM: Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57BL/6 mice. Cancer Res 44: 717–726, 1984.
Golakoti T, Ohtani I, Patterson GML, Moore RE, Corbett TH, Valeriote FA, Demchik L: Total structures of cryptophycins, potent antitumor depsipeptides from the blue-green alga Nostoc sp Strain GSV 224. J Am Chem Soc 116: 4729–4737, 1994.
Golakoti T, Ogino J, Heltzel CE, Husebo TL, Jensen CM, Larsen LK, Patterson GML, Moore RE, Mooberry SL, Corbett TH, Valeriote FA: Structure determination, conformational analysis, chemical stability studies and antitumor evaluation of the cryptophycins. Isolation of eighteen new analogs from Nostoc sp. Strain GSV 224. J Am Chem Society 117(49): 12030–12049, 1995.
Corbett TH, Valeriote FA, Demchik L, Polin L, Panchapor C, Pugh S, White K, Kushner J, Jones J, Jones L, Foster B, Wiegand R, Lisow L, Golakoti T, Heltzel C, Ogino J, Patterson G, Moore R: Preclinical anticancer activity of cryptophycin-8. J Exp Ther Oncol 1: 95–108, 1996.
Corbett T, Valeriote F, Baker L, et al: Antitumor activity of N-[[1-[[2-(Diethylamino)ethyl]amino]-9-oxo-9II-Thioxanthen-4-Y]methyl]methanesulfonamide (WIN33377) and analogs: Expert opinion on Investigational Drugs 3(12): 1281–1292, 1994.
Horwitz JP, Massova I, Wiese TE, Bessler BH, Corbett TH: Comparative molecular field analysis of the antitumor activity of 9H-thioxanthen-9-ones against pancreatic ductal carcinoma. J Med Chem 37: 781–876, 1994.
Wentland MP, Perni RB, Powles RG, Hlavac AG, Mattes KC, Corbett TH, Coughlin SA, Rake JB: Anti-solid tumor efficacy and preparation of N-[[1-[[2-(Diethylamino)Ethyl]Amino]-9-OXO-9H-Thioxanthen-4-YL] Methyl] Methanesulonamide (WIN33377) and related derivatives. Bioorg Med Chem Lett 4(4): 609–614, 1994.
Schabel JR FM, Griswold Jr DP, Corbett TH, Laster Jr WR, Mayo JC, Lloyd HH: 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 on potential clinical utility for treatment of advanced solid tumors of man. In: Cancer Drug Development. Part B. Methods in Cancer Research, Vol 17, H Busch and V DeVita Jr (eds), Academic Press Inc, New York, pp 3–51, 1979.
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Corbett, T.H., Valeriote, F.A., Demchik, L. et al. Discovery of cryptophycin-1 and BCN-183577: Examples of strategies and problems in the detection of antitumor activity in mice. Invest New Drugs 15, 207–218 (1997). https://doi.org/10.1023/A:1005875015011
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DOI: https://doi.org/10.1023/A:1005875015011