Protection by WR-2721 of the toxicity induced by the combination of cisplatin and 5-fluorouracil.
We evaluated the effects of WR-2721 and its metabolite WR-1065 on in vitro growth inhibition by 5-fluorouracil (5FU) and cisplatin (CDDP) and the effect of WR-2721 on in vivo toxicity and antitumor effect of 5FU and CDDP. In cell culture both WR-2721 and WR-1065 were not able to reverse growth inhibition caused by either 5FU or CDDP. Administration of WR-2721 i.p. at 525 mg/kg to mice resulted in a severe temperature drop to 27 degrees C; at 200 mg/kg hypothermia was less severe. WR-2721 failed to prevent 5FU toxicity, but the maximum tolerated dose of CDDP in the combination with 5FU (at 100 mg/kg) could be increased from 3 to 7 mg/kg. CDDP at 7 mg/kg enhanced leukopenia caused by 5FU at 100 mg/kg to 20% and thrombocytopenia to 40%; WR-2721 reduced leukopenia and prevented thrombocytopenia induced by the combination. Combination of CDDP, 5FU, and WR-2721 resulted in an enhanced antitumor activity against the murine colon tumor Colon 26 compared to 5FU alone and to 5FU combined with CDDP at their maximum tolerated dose.
Peters
G J
GJ
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
van der Wilt
C L
CL
Gyergyay
F
F
van Laar
J A
JA
Treskes
M
M
van der Vijgh
W J
WJ
Pinedo
H M
HM
D004999:Amifostine / Q000627:therapeutic use*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin / Q000633:toxicity*; D005260:Female; D005472:Fluorouracil / Q000633:toxicity*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
D004999:Amifostine; D002945:Cisplatin; D005472:Fluorouracil