Abstract
Recent data have shown that the in vitro and in vivo cytotoxicity of bioreductive drugs could be significantly increased when combined with chemotherapy drugs such as cisplatinum, depending on the timing of administration. 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 xenografted human tumours: a rectal carcinoma (HRT18) and a melanoma (Na11+). Animal lethality was markedly increased when tirapazamine at the lethal dose 10% was combined with the other drugs. For the HRT18 tumour the combination of tirapazamine and bleomycin significantly increased the delay of regrowth compared with bleomycin alone (P = 0.04) and was more cytotoxic than tirapazamine alone (P = 0.04). For the Na11+ tumours the 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 alone (P = 0.0001). When compared with c-DDP or tirapazamine alone, there was 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 be cytotoxic against clonogenic human tumour cells. Its efficacy in vivo may depend on its combination with already active chemotherapy drugs on the tumour model used. The timing of administration may be less important than previously thought.
Highlights
One of the main problems in the treatment of cancer is to define therapeutic approaches directed against tumour cells, and which are non-toxic for normal cells
For the Nall+ tumours the combination of tirapazamine with VP16 significantly increased tumour doubling time compared with the controls (P=0.001) or VP16 alone
Bleo and DTIC are preferentially toxic to aerobic cells and 5-FU and c-DDP have no selective toxicity based on cellular oxygenation (Teicher et al, 1981)
Summary
All the drugs were injected intraperitoneally (i.p.). Tirapazamine (3-amino-1,2,4-benzotriazinel,4-dioxide, SR-4233, WIN 59075, supplied by Sterling Drug), c-DDP (Roger Bellon) and Effect d tbiau-d-e- on xenrafted hIa umnows E Lartigau ad M Gudcd. To mimic common clinical practice, the drugs were injected alone or in combination for four successive days, except c-DDP, which was injected only once. Tirapazamine was injected immediately before or 3 h before the other drug. A protocol based on previously published studies (single day injection) (Dorie and Brown 1993). The effect of the different treatments on the relative clonogenicity was calculated as the product of plating efficiency and tumour cell yield for treated tumours relative to that for control untreated tumours assayed i\n parallel. The cell yield and plating efficiency were compared using a non-parametric Mann-Whitney test
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