THE EFFECT OF TIRAPAZAMINE (SR-4233) ALONE OR COMBINED WITH CHEMOTHERAPEUTIC-AGENTS ON XENOGRAFTED HUMAN TUMORS

Recent data have shown that the in vitro and in vivo cytotoxicity of b ioreductive drugs could be significantly increased when combined with chemotherapy drugs such as cisplatinum, depending on the timing of adm inistration. The aim of this study was to define the toxicity (animal lethality) and the activity (growth delay assay, excision assay) of a bioreductive drug, tirapazamine, alone and combined with chemotherapy agents (5-FU, VP16, bleo, DTIC and c-DDP) on nude mice bearing xenogra fted human tumours: a rectal carcinoma (HRT18) and a melanoma (Na11+). Animal lethality was markedly increased when tirapazamine at the leth al dose 10% was combined with the other drugs. For the HRT18 tumour th e combination of tirapazamine and bleomycin significantly increased th e delay of regrowth compared with bleomycin alone (P=0.04) and was mor e cytotoxic than tirapazamine alone (P=0.04). For the Na11+ tumours th e combination of tirapazamine with VP16 significantly increased tumour doubling time compared with the controls (P=0.001) or VP16 alone. The combination of tirapazamine and VP16 was more cytotoxic than VP16 alo ne (P=0.0001). When compared with c-DDP or tirapazamine alone, there w as a significant decrease in plating efficiency when tirapazamine and c-DDP were given at the same time (P=0.04), but not when tirapazamine was given 3 h before c-DDP. In conclusion, tirapazamine was shown to b e cytotoxic against clonogenic human tumour cells. Its efficacy in viv o may depend on its combination with already active chemotherapy drugs on the tumour model used. The timing of administration may be less im portant than previously thought.