title: TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules.
abstract: OBJECTIVE
  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.
authors.affiliation: Threshold Pharmaceuticals, 170 Harbor Way, Suite 300, South San Francisco, CA 94080, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Sun
authors.forename: Jingli
authors.initials: J
authors.lastname: Wang
authors.forename: Dharmendra
authors.initials: D
authors.lastname: Ahluwalia
authors.forename: Amanda F
authors.initials: AF
authors.lastname: Baker
authors.forename: Lee D
authors.initials: LD
authors.lastname: Cranmer
authors.forename: Damien
authors.initials: D
authors.lastname: Ferraro
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Duan
authors.forename: W Steve
authors.initials: WS
authors.lastname: Ammons
authors.forename: John G
authors.initials: JG
authors.lastname: Curd
authors.forename: Mark D
authors.initials: MD
authors.lastname: Matteucci
authors.forename: Charles P
authors.initials: CP
authors.lastname: Hart
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077143:Docetaxel; D004353:Drug Evaluation, Preclinical; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D016513:Mice, SCID; D009593:Nitroimidazoles / Q000008:administration & dosage*; D000068437:Pemetrexed; D010752:Phosphoramide Mustards / Q000008:administration & dosage*; D011355:Prodrugs / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D005971:Glutamates; D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; D011355:Prodrugs; C552526:TH 302; D043823:Taxoids; D000068437:Pemetrexed; D003841:Deoxycytidine; D000077143:Docetaxel; D006147:Guanine; D000077146:Irinotecan; D002945:Cisplatin; D002166:Camptothecin; D000093542:Gemcitabine