Clonogenic response of cells of murine intestinal crypts to 12 cytotoxic drugs

Abstract

The in situ response of clonogenic cells in murine intestinal crypts to graded doses of 12 clinically used cytotoxic drugs has been measured by the crypt microcolony assay. For the alkylating agents mechlorethamine hydrochloride and BCNU, survival curves down to three logs of crypt depletion could be obtained. However, with isopropyl methane sulphonate only one log of depletion was measurable, and for a fourth alkylating agent, cyclophosphamide, no crypt killing occurred before other toxicities resulted in death of the animal in less than 3-4 days. This is the major constraint on the use of the microcolony assay with cytotoxic drugs. Of four antibiotics, survival curves were obtainable for adriamycin, bleomycin and mitomycin C, but not for actinomycin D. 5-Fluorouracil gave only a limited degree of crypt kill. Of three S-phase-specific drugs, hydroxyurea and vincristine resulted in little or no crypt depletion, but there was dose-dependent crypt depletion after methotrexate. The complexities of applying cellular-kinetic classifications of cytotoxic drugs to in situ endpoints are discussed.