tirapazamine and Rectal-Neoplasms

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.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cell Division; Cisplatin; Dacarbazine; Drug Screening Assays, Antitumor; Etoposide; Fluorouracil; Humans; Melanoma; Mice; Mice, Nude; Rectal Neoplasms; Tirapazamine; Transplantation, Heterologous; Triazines

Solid tumours contain hypoxic cells which are resistant to radiotherapy. This study compares the efficacy of several strategies to counteract diffusion-limited hypoxia, or intermittent hypoxia in a fractionated regimen of 1 to 6 x 2 Gy.. Nicotinamide (250 mg/kg), perflubron emulsion (Oxygent) (4 ml/kg), tirapazamine (SR4233) (0.10 mmol/kg) and carbogen breathing, administered alone or in combination, were investigated on two tumour cell lines: EMT6 (a rodent mammary carcinoma) and HRT18 (a human rectal adenocarcinoma) using a clonogenic assay. The radiosensitizing effect of the agents was assessed after 1 and 6 x 2 Gy for drugs used alone, and 1, 2, 4, 6 x 2 Gy for drugs used in combination.. At the end of the fractionated radiation regimen, the combination of nicotinamide + carbogen induced the greatest radiosensitization for EMT6 tumours, while greatest radiosensitization of HRT18 was obtained with nicotinamide + carbogen + tirapazamine.. The efficacy of the strategies for overcoming hypoxia using a fractionated regimen depends on the tumour cell line. These differences could be linked to differences in the initial percentages of acute and chronic hypoxic cells, and to changes in the two types of hypoxia during treatment.

Topics: Adenocarcinoma; Animals; Carbon Dioxide; Cell Hypoxia; Emulsions; Female; Fluorocarbons; Humans; Hydrocarbons, Brominated; Mammary Neoplasms, Experimental; Mice; Niacinamide; Oxygen; Radiation Tolerance; Radiation-Sensitizing Agents; Radiotherapy; Radiotherapy Dosage; Rectal Neoplasms; Tirapazamine; Triazines; Tumor Cells, Cultured