[MOL] Cancer Chemotherapy and Pharmacology..... [00027] Medicine On Line

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[MOL] Cancer Chemotherapy and Pharmacology.....

Cancer Chemotherapy and Pharmacology

ISSN: 0344-5704 (printed version)
ISSN: 1432-0843 (electronic version)

Table of Contents

Abstract Volume 43 Issue 5 (1999) pp 402-408

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

Steven Weitman (1)(2), Gina Mangold (1), Jennifer Marty (1), Daniel Dexter (1), Susan Hilsenbeck (2), James Rake (3), Paul Juniewicz (3), Daniel Von Hoff (1)(2)

(1) Institute for Drug Development, 14960 Omicron Drive, San Antonio, TX 78245-3217, USA
(2) University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7810, USA Tel.: 210-567-5265; Fax: 210-567-5339
(3) Sanofi Pharmaceuticals, Inc., 9 Great Valley Parkway, Malvern, PA 19355, USA

Received: 20 May 1998 / Accepted: 3 September 1998

Abstract Purpose: Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide; SR 4233) is a bioreductive agent that exhibits relatively selective cytotoxicity towards 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 three-way combination studies using the MV-522 human lung carcinoma xenograft model. Methods: Agents were administered as a single i.p. bolus, with tirapazamine being given 3 h prior to paclitaxel, paraplatin, or their combination. Tumor growth inhibition (TGI), final tumor weights, partial and complete responses, and time to tumor doubling were determined after drug administration. 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 include tirapazamine. The addition of tirapazamine to paclitaxel-paraplatin therapy resulted in a 50% complete response rate; there were no complete responses seen when only the paclitaxel-paraplatin combination was administered. Time to tumor doubling was also significantly improved with the addition of tirapazamine to the paclitaxel 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: These results are important since recent studies have suggested that the combination of paclitaxel and paraplatin may be particularly active in patients with advanced stage non-small-cell lung cancer. Since tirapazamine can significantly improve efficacy, but does not appear to enhance the toxicity of paclitaxel and paraplatin, its evaluation in future clinical trials in combination with paclitaxel-paraplatin-based therapy appears warranted.

Key words Tirapazamine Lung cancer Platinum Taxol

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