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Single-Agent Chemotherapy of a Solid Murine Tumor Assayed by Growth Delay and Cell Survival¹

Department of Radiation Oncology, University of California, San Francisco, California 94143

A study was made of the sensitivity of the EMT6/SF tumor in BALB/c mice to X-rays and eight chemotherapeutic agents in preparation for subsequent combination studies using drugs and X-rays. The drugs tested were: actinomycin D; 1,3-bis(2-chloroethyl)-1-nitrosourea, bleomycin; cis-diamminedichloroplatinum(II); cyclophosphamide; 5-fluorouracil; methotrexate; and vincristine. Drug efficacy was tested by using an in vitro cell survival assay after treatment in vivo and by growth delay of tumors in situ. Cyclophosphamide was the most effective drug; vincristine was the least effective drug at maximum tolerated doses when assayed by growth delay. Infromation relating to pharmacokinetics, time of drug action, and the presence or absence of possible repair processes was obtained from experiments in which cell survival was assayed at different times after treatment in situ. 1,3-bis(2-chloroethyl)-1-nitrosourea, bleomycin, cis-diamminedichloroplatinum(II), and Cytoxan (cyclophosphamide) all showed increases in survival following surviving fraction minima, suggesting that repair of drug-induced damage occurred. For bleomycin, as has been shown here and by other workers, the surviving fraction increase was largely an artifact, but this was not the case for cis-diamminedichloroplatinum(II). The ability of each drug to kill all the different subpopulations of cells in EMT6/SF tumors was tested by obtaining dose-response curves. Exponential survival curves were seen for 1,3-bis(2-chloroethyl)-1-nitrosourea, Cytoxan (cyclophosphamide), actinomycin D, 5-fluorouracil, and methotrexate, although due to the ineffectiveness of the last three drugs listed, low enough surviving fractions were not reached to rule out the possibility of a plateau of response. cis-diamminedichloroplatinum(II) showed evidence of a threshold before exponential killing was attained, while bleomycin showed a plateau indicating a resistant subpopulation. Discrepancies between the growth delay and in vivo-in vitro assays were shown by significant difference in growth delay produced by drugs causing the same amount of cell killing.

¹ Work performed under NIH Grant CA-20529.

² To whom requests for reprints should be addressed, at Gray Laboratory, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN, England.

Received 7/12/78. Accepted 10/ 1/79.

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