Interaction of SR-4233 with hyperthermia and radiation in the FSaIIC murine fibrosarcoma tumor system in vitro and in vivo.
The effects of SR-4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide), a hypoxic cell cytotoxic agent, were assayed against the FSaIIC murine fibrosarcoma in vitro and in vivo alone and in conjunction with hyperthermia and radiation. In vitro, a concentration of 500 microM of SR-4233 upon exposure of the cells for 1 h decreased the survival of hypoxic cells by about 1 log more than euoxic cells at 37 degrees C and pH 7.40. At the same concentration at pH 6.45, this difference in cytotoxicity increased to about 3 logs. In conjunction with 42 or 43 degrees C hyperthermia at pH 7.40, the killing of both euoxic and hypoxic cells was markedly increased (hypoxic greater than oxic), and the effect of hyperthermia on SR-4233 cytotoxicity was further increased at pH 6.45. SR-4233 proved to be an effective radiosensitizer of hypoxic cells in vitro, producing an enhancement ratio of 2.6 +/- 0.2 at pH 7.40 and 2.7 +/- 0.2 at pH 6.45. In vivo, however, SR-4233 (50 mg/kg) used with single dose radiation (10, 20, or 30 Gy) did not alter the slope of the radiation dose-dependent tumor growth delay curve but did produce a significant additive increase in tumor growth delay. Local hyperthermia (43 degrees C, 30 min) plus SR-4233 (30 mg/kg) produced a tumor growth delay of 9.1 +/- 2.2 days, whereas SR-4233 alone caused a tumor growth delay of only 1.7 +/- 0.9 days and the hyperthermia, only 1.4 +/- 0.7 days. The tumor growth delay increased to 28.2 +/- 4.4 days with the addition of daily radiation (3 Gy for 5 days) to SR-4233 and hyperthermia given on treatment day 1 only. Hoechst 33342 dye-selected tumor subpopulation analysis at 24 h following treatment demonstrated that SR-4233 (30 mg/kg) was more toxic to dim (presumably hypoxic) cells by about 1.8-fold. The addition of hyperthermia to treatment with SR-4233 increased the killing of dim cells by about 5-fold but of bright cells by only 2-fold. Trimodality treatment with SR-4233, hyperthermia, and radiation increased the killing of bright cells by about 6.5-fold and of dim cells by about 16.5-fold as compared with radiation alone. These results indicate that SR-4233 might be used quite effectively with radiation and/or hyperthermia to treat tumors with significant hypoxic subpopulations.
Herman
T S
TS
Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
Teicher
B A
BA
Coleman
C N
CN
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D005434:Flow Cytometry; D006358:Hot Temperature; D006863:Hydrogen-Ion Concentration; D006979:Hyperthermia, Induced; D000860:Hypoxia; D007700:Kinetics; D051379:Mice; D008809:Mice, Inbred C3H; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000166:cytology* / Q000187:drug effects / Q000528:radiation effects
D000970:Antineoplastic Agents; D014227:Triazines; D000077704:Tirapazamine