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

Steven D Weitman, Gina Mangold, Jennifer Marty, Daniel Dexter, Susan Hilsenbeck, James Rake, Paul Juniewicz, Daniel Von Hoff

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)402-408
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume43
Issue number5
DOIs
StatePublished - 1999

Fingerprint

tirapazamine
Carboplatin
Paclitaxel
Heterografts
Lung Neoplasms
Tumors
Neoplasms
MV protocol 2
Toxicity
Animals

Keywords

  • Lung cancer
  • Platinum
  • Taxol
  • Tirapazamine

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Evidence of enhanced in vivo activity using tirapazamine with paclitaxel and paraplatin regimens against the MV-522 human lung cancer xenograft. / Weitman, Steven D; Mangold, Gina; Marty, Jennifer; Dexter, Daniel; Hilsenbeck, Susan; Rake, James; Juniewicz, Paul; Von Hoff, Daniel.

In: Cancer Chemotherapy and Pharmacology, Vol. 43, No. 5, 1999, p. 402-408.

Research output: Contribution to journalArticle

Weitman, Steven D ; Mangold, Gina ; Marty, Jennifer ; Dexter, Daniel ; Hilsenbeck, Susan ; Rake, James ; Juniewicz, Paul ; Von Hoff, Daniel. / Evidence of enhanced in vivo activity using tirapazamine with paclitaxel and paraplatin regimens against the MV-522 human lung cancer xenograft. In: Cancer Chemotherapy and Pharmacology. 1999 ; Vol. 43, No. 5. pp. 402-408.
@article{832f88b763e34bee83cde67ce39b4b10,
title = "Evidence of enhanced in vivo activity using tirapazamine with paclitaxel and paraplatin regimens against the MV-522 human lung cancer xenograft",
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.",
keywords = "Lung cancer, Platinum, Taxol, Tirapazamine",
author = "Weitman, {Steven D} and Gina Mangold and Jennifer Marty and Daniel Dexter and Susan Hilsenbeck and James Rake and Paul Juniewicz and {Von Hoff}, Daniel",
year = "1999",
doi = "10.1007/s002800050914",
language = "English (US)",
volume = "43",
pages = "402--408",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "5",

}

TY - JOUR

T1 - Evidence of enhanced in vivo activity using tirapazamine with paclitaxel and paraplatin regimens against the MV-522 human lung cancer xenograft

AU - Weitman, Steven D

AU - Mangold, Gina

AU - Marty, Jennifer

AU - Dexter, Daniel

AU - Hilsenbeck, Susan

AU - Rake, James

AU - Juniewicz, Paul

AU - Von Hoff, Daniel

PY - 1999

Y1 - 1999

N2 - 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.

AB - 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.

KW - Lung cancer

KW - Platinum

KW - Taxol

KW - Tirapazamine

UR - http://www.scopus.com/inward/record.url?scp=0032988624&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032988624&partnerID=8YFLogxK

U2 - 10.1007/s002800050914

DO - 10.1007/s002800050914

M3 - Article

C2 - 10100596

AN - SCOPUS:0032988624

VL - 43

SP - 402

EP - 408

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 5

ER -