The therapeutic impact of dipyridamole: chemopotentiation of the cytotoxic combination 5-fluorouracil/cisplatin in an animal model of human bladder cancer.
Using an in vivo assay of tumor cytotoxicity (the subrenal capsule assay in nude mice), two therapeutic strategies for the treatment of advanced human transitional cell carcinoma have been evaluated: 1) the use of 5-fluorouracil in combination with cisplatin and 2) the ability of the chemosensitizer dipyridamole to augment the cytotoxicity of CDDP and 5FU. A moderate cytotoxic response of human TCC line DU-4284 to single agent CDDP was seen; it was dose dependent at minimally toxic doses [maximal cytotoxicity--27% tumor survival (%TS) relative to control]. Efficacy was further significantly enhanced by the addition of DP [11%TS (p = .008)]. 5FU at minimally toxic doses (100 and 150 mg./kg.) also demonstrated moderate dose-dependent cytotoxic activity (35 and 31%TS, respectively) which was further enhanced by DP [21%TS (p = .03) and 18%TS (p = .05)]. A constant dose ratio of CDDP/5FU when diluted showed dose-dependent cytotoxicity; at the highest dose dilution studied, substantial cytotoxic efficacy (17%TS) was attained. The cytotoxicity of 5FU/CDDP was order independent (p = .95). The addition of DP to this combination (5FU/CDDP) further enhanced efficacy; host toxicity was not substantially enhanced. A multiple regression analysis confirmed a statistically significant effect of DP with both CDDP and 5FU (p = .001 and 0.0001, respectively); tests for trend showed no significant interaction (p = 0.33 for all models). It is concluded that, in this preclinical in vivo model of human bladder cancer, 1) CDDP and 5FU show substantial enhanced efficacy when combined, and 2) DP serves as an in vivo chemosensitizer of both CDDP and 5FU; DP further augments the efficacy of this binary combination. These data would indicate the potential of this ternary (5FU/CDDP/DP) drug therapeutic regimen for clinical trial to treat advanced bladder cancer.
Department of Surgery (Urology), Duke University School of Medicine, Durham, North Carolina.
T E
TE
Keane
G L
GL
Rosner
J R
JR
Gingrich
S H
SH
Poulton
P J
PJ
Walther
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002460:Cell Line; D002945:Cisplatin / Q000008:administration & dosage; D004176:Dipyridamole / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D013370:Subrenal Capsule Assay; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
D004176:Dipyridamole; D002945:Cisplatin; D005472:Fluorouracil