EFFECTS OF CYTOTOXIC CHEMOTHERAPEUTIC-AGENTS ON SPLIT-DOSE REPAIR IN INTESTINAL CRYPT CELLS

Purpose: Many cancer chemotherapeutic agents interact with radiation t o enhance the amount of radiation damage observed in both tumor and no rmal tissues, It is important to predict this interaction and to deter mine the effect of drug on sublethal damage repair, To evaluate for ef fects in rapid renewing normal tissues, the intestinal crypt cell in v ivo assay is an excellent one to employ, These studies investigate the effect of eleven cancer chemotherapeutic drugs on split-dose repair i n the intestinal crypt cell of the mouse. Methods and Materials: LAF1 male mice, age 10-12 weeks, were exposed to whole-body irradiation wit h orthovoltage x-rays delivered as a single dose or as equally divided doses delivered with intervals between the two exposures of 2 to 24 h , In the experimental group, the cancer chemotherapeutic agent was adm inistered intraperitoneally 2 h before the first radiation dose, At 3. 6 days after the second irradiation, the mice were sacrificed; the jej unum was removed, fixed, and sectioned for light microscopy, The numbe r of regenerating crypts were counted and corrected to represent the n umber of surviving cells per circumference. Results: Of the eleven dru gs tested, only carmustine eliminated split-dose repair, Cisplatin del ayed repair, and methotrexate caused marked synchronization obliterati ng the observation of split-dose repair. Conclusions: Most cytotoxic c hemotherapeutic agents do not inhibit sublethal damage repair in intes tinal crypt cells when given 2 h before the first radiation exposure, Absence of the initial increase in survival seen with split-dose radia tion is noted with carmustine and high-dose methotrexate. (C) 1997 Els evier Science Inc.