Evidence of enhanced in vivo activity using tirapazamine with paclitaxel and paraplatin regimens against the MV-522 human lung cancer xenograft

Purpose: Tirapazamine (3-amino-1,2,4-benzo- iazine 1,4-dioxide: SR 4233) is a bioreductive agent that exhibits relatively selective cytotoxicity towar ds cells under hypoxic conditions and can enhance the antitumor activity of many standard oncolytics. In the present study we examined the interaction between tirapazamine in vivo with paclitaxel and paraplatin in two- and th ree-way combination studies using the MV-522 human lung carcinoma xenograft model, Methods: Agents were administered as a single i.p. bolus with tirap azamine being given 3h prior to paclitaxel, paraplatin, or their combinatio n. Tumor growth inhibition (TGI), final tumor weights, partial and complete responses, and time to tumor doubling were determined after drug administr ation. Results: Tirapazamine as a single agent was ineffective against this human lung tumor model. A substantial increase in TGI was seen in animals treated with the triple-agent regimen (tirapazamine -paclitaxel-paraplatin) compared to animals treated with double-agent regimens that did not includ e tirapazamine. The addition of tirapazamine to paclitaxel-paraplatin thera py resulted in a 50% complete response rate; there were no complete respons es seen when only the paclitaxel-paraplatin combination was administered. T ime to tumor doubling was also significantly improved with the addition of tirapazamine to the palitaxel and paraplatin combinations. Tirapazamine did not increase the toxicity of paclitaxel, paraplatin, or their combinations as judged by its minimal impact: on body weight and the fact that no toxic deaths were observed with tirapazamine-containing regimens. Conclusions: T hese results are important since recent studies have suggested that the com bination of paclitaxel and paraplatin may be particularly active in patient s with advanced stage non-small-cell lung cancer. Since tirapazamine can si gnificantly improve efficacy, but does not appear to enhance the toxicity o f paclitaxel and paraplatin, its evaluation in future clinical trials in co mbination with paclitaxel-paraplatin-based therapy appears warranted.