CLINICAL PREDICTIVITY OF TRANSPLANTABLE TUMOR SYSTEMS IN THE SELECTION OF NEW DRUGS FOR SOLID TUMORS - RATIONALE FOR A 3-STAGE STRATEGY

  • 1 January 1983
    • journal article
    • research article
    • Vol. 67  (9) , 753-765
Abstract
The strategy used for the discovery of potentially clinically effective drugs by means of transplantable tumor systems in mice is analyzed. With the present strategy used by the National Cancer Institute and the European Organization for Research on Treatment of Cancer, most new compounds are initially tested in the P388 [mouse] leukemia model. Drugs showing activity in this prescreen are subsequently evaluated in a panel of 8 screens (B16, CD8, Co38, L1210, LL, CX-1, LX-1 and MX-1 [respectively, murine melanoma, mammary tumor, colon tumor, leukemia, and lung tumor lines and human colon tumor, lung tumor and breast tumor lines]). Positivity in any screen qualifies a new drug for further preclinical studies leading to phase I-II clinical trial. Analyses of the experimental screening data for 1949 compounds and the comparison of results in humans and mice for 69 drugs that were clinically evaluated against solid tumors, indicated that the correlation of screening and clinical results is low and that a modified approach using 4 systems (P388, B16, L1210 and MX-1) would be sufficient to uncover most of the drugs presently shown to be clinically active. To take advantage also of the information provided by other screens of the panel, a 3-stage strategy can be used. In the 1st stage, compounds would be tested in the P388 prescreen, with a slightly higher level of response being required (T/C% [computed as the mean (or median) survival time of treated (T) mice divided by that for the controls (C)] .gtoreq. 125 instead of 120). In the 2nd stage, prescreen-positive drugs would be tested in the B16, L1210 and MX-1 systems. Drugs positive in any one of these screens would then be tested in Co38, LL and CX-1 to determine priorities for clinical study. For new chemical structures of particular promise, this 3rd stage could be dropped. LX-1 and CD8 are not useful in this context. Such a strategy would be much more economical and faster than the automatic use of 9 systems, and the resultant savings should permit the discovery of an increased number of potentially active compounds.

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