Journal article
Hypoxia-specific drug tirapazamine does not abrogate hypoxic tumor cells in combination therapy with irinotecan and methylselenocysteine in well-differentiated human head and neck squamous cell carcinoma An253 xenografts
Neoplasia (New York, N.Y.), Vol.10(8), pp.857-865
08/01/2008
DOI: 10.1593/neo.08424
PMCID: PMC2481573
PMID: 18670644
Abstract
Well-differentiated hypoxic regions in head and neck squamous cell carcinoma like in A253 xenografts are avascular and, therefore, hinder drug delivery leading to drug resistance and tumor regrowth. Methylselenocysteine ( MSC, 0.2 mg/mouse per day per oral for 35 days starting 7 days before the first irinotecan (CPT-11)) has been found to increase efficacy of a wide variety of chemotherapeutic agents including CPT-11 ( 100 mg/kg per week x 4 intravenously). Whereas CPT-11 leads to a 10% complete response (CR) in A253 xenografts, the combination of MSC and CPT-11 increased the CR to 70%. Surviving tumors were found to consist largely of avascular hypoxic regions. Here, we investigated the combination of tirapazamine (TPZ, 70 mg/kg per week intraperitoneal x 4 administered 3 or 72 hours before CPT-11), a bioreductive drug in clinical trial with selective toxicity for hypoxic cells, with MSC and CPT-11 in further enhancing the cure rates. Tumor response, change in tumor hypoxic regions, and DNA damage were monitored in vivo. Tirapazamine administered 3 hours before CPT-11 in combination with MSC + CPT-11 led to a lower tumor burden. Tirapazamine did not increase cure rate beyond that of MSC + CPT-11 combination and was instead found to decrease cures with no evidence of an increased DNA damage or a significant reduction in avascular hypoxic tumor regions. CD31 immunostaining in A253 demonstrated disruption of tumor vessels by TPZ that could lower cytotoxic drug delivery to carbonic anhydrase IX-positive hypoxic tumor cells and may explain at least partially these unexpected results.
Details
- Title: Subtitle
- Hypoxia-specific drug tirapazamine does not abrogate hypoxic tumor cells in combination therapy with irinotecan and methylselenocysteine in well-differentiated human head and neck squamous cell carcinoma An253 xenografts
- Creators
- Arup Bhattacharya - Roswell Park Cancer InstituteKaroly Toth - Roswell Park Cancer InstituteFarukh A. Durrani - Roswell Park Cancer InstituteShousong Cao - Roswell Park Cancer InstituteHarry K. Slocum - Roswell Park Cancer InstituteSreenivasulu Chintala - Roswell Park Cancer InstituteYoucef M. Rustum - Roswell Park Cancer Institute
- Resource Type
- Journal article
- Publication Details
- Neoplasia (New York, N.Y.), Vol.10(8), pp.857-865
- DOI
- 10.1593/neo.08424
- PMID
- 18670644
- PMCID
- PMC2481573
- NLM abbreviation
- Neoplasia
- ISSN
- 1522-8002
- eISSN
- 1476-5586
- Publisher
- NEOPLASIA PRESS
- Number of pages
- 9
- Grant note
- P30CA016056 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) P30 CA016056; CA016056 / NCI NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 08/01/2008
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359661802771
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