TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: Optimization of dosing regimens and schedules

Qian Liu, Jessica D. Sun, Jingli Wang, Dharmendra Ahluwalia, Amanda F Baker, Lee D Cranmer, Damien Ferraro, Yan Wang, Jian Xin Duan, W. Steve Ammons, John G. Curd, Mark D. Matteucci, Charles P. Hart

Research output: Contribution to journalArticle

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Abstract

Purpose: Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Methods: Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH- 302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. Results: The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2-8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. Conclusions: TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302.

Original languageEnglish (US)
Pages (from-to)1487-1498
Number of pages12
JournalCancer Chemotherapy and Pharmacology
Volume69
Issue number6
DOIs
StatePublished - Jun 2012

Fingerprint

Prodrugs
Appointments and Schedules
irinotecan
temozolomide
docetaxel
gemcitabine
Pemetrexed
Toxicity
Tumors
Heterografts
Therapeutics
Non-Small Cell Lung Carcinoma
Doxorubicin
Colonic Neoplasms
Cisplatin
Neoplasms
Prostatic Neoplasms
Drug Administration Schedule
TH 302
Hypoxia

Keywords

  • Combination chemotherapy
  • Human tumor xenograft
  • Hypoxia-activated prodrug
  • TH-302
  • Tumor hypoxia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy : Optimization of dosing regimens and schedules. / Liu, Qian; Sun, Jessica D.; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F; Cranmer, Lee D; Ferraro, Damien; Wang, Yan; Duan, Jian Xin; Ammons, W. Steve; Curd, John G.; Matteucci, Mark D.; Hart, Charles P.

In: Cancer Chemotherapy and Pharmacology, Vol. 69, No. 6, 06.2012, p. 1487-1498.

Research output: Contribution to journalArticle

Liu, Qian ; Sun, Jessica D. ; Wang, Jingli ; Ahluwalia, Dharmendra ; Baker, Amanda F ; Cranmer, Lee D ; Ferraro, Damien ; Wang, Yan ; Duan, Jian Xin ; Ammons, W. Steve ; Curd, John G. ; Matteucci, Mark D. ; Hart, Charles P. / TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy : Optimization of dosing regimens and schedules. In: Cancer Chemotherapy and Pharmacology. 2012 ; Vol. 69, No. 6. pp. 1487-1498.
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T1 - TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy

T2 - Optimization of dosing regimens and schedules

AU - Liu, Qian

AU - Sun, Jessica D.

AU - Wang, Jingli

AU - Ahluwalia, Dharmendra

AU - Baker, Amanda F

AU - Cranmer, Lee D

AU - Ferraro, Damien

AU - Wang, Yan

AU - Duan, Jian Xin

AU - Ammons, W. Steve

AU - Curd, John G.

AU - Matteucci, Mark D.

AU - Hart, Charles P.

PY - 2012/6

Y1 - 2012/6

N2 - Purpose: Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Methods: Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH- 302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. Results: The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2-8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. Conclusions: TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302.

AB - Purpose: Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Methods: Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH- 302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. Results: The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2-8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. Conclusions: TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302.

KW - Combination chemotherapy

KW - Human tumor xenograft

KW - Hypoxia-activated prodrug

KW - TH-302

KW - Tumor hypoxia

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