title: Low-dose metronomic daily cyclophosphamide and weekly tirapazamine: a well-tolerated combination regimen with enhanced efficacy that exploits tumor hypoxia.
abstract: The recent clinical successes of antiangiogenic drug-based therapies have also served to highlight the problem of acquired resistance because, similar to other types of cancer therapy, tumors that initially respond eventually stop doing so. Consequently, strategies designed to delay resistance or treat resistant subpopulations when they arise have assumed considerable importance. This requires a better understanding of the various possible mechanisms for resistance. In this regard, reduced oxygenation is thought to be a key mediator of the antitumor effects of antiangiogenic therapies; accordingly, increased hypoxia tolerance of the tumor cells presents a potential mechanism of resistance. However, hypoxia can also be exploited therapeutically through the use of hypoxic cell cytotoxins, such as tirapazamine. With this in mind, we measured the oxygenation of PC-3 human prostate cancer xenografts subjected to chronic low-dose metronomic (LDM) antiangiogenic chemotherapy using cyclophosphamide given through the drinking water. We found that LDM cyclophosphamide impairs the oxygenation of PC-3 xenografts even during relapse, coinciding with reduced microvessel density. Combination of LDM cyclophosphamide with tirapazamine results in significantly improved tumor control in the PC-3, HT-29 colon adenocarcinoma, and MDA-MB-231 breast cancer human xenograft models without having a negative effect on the favorable toxicity profile of LDM cyclophosphamide. These results provide further evidence that reduced vascular dependence/increased hypoxia tolerance may be a basis for eventual resistance of tumors exposed to long-term LDM chemotherapy.
authors.affiliation: Molecular and Cellular Biology Research and Toronto-Sunnybrook Regional Cancer Centre, Sunnybrook and Women's College Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
authors.forename: Urban
authors.initials: U
authors.lastname: Emmenegger
authors.forename: Gerard C
authors.initials: GC
authors.lastname: Morton
authors.forename: Giulio
authors.initials: G
authors.lastname: Francia
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shaked
authors.forename: Marcela
authors.initials: M
authors.lastname: Franco
authors.forename: Adina
authors.initials: A
authors.lastname: Weinerman
authors.forename: Shan
authors.initials: S
authors.lastname: Man
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000633:toxicity; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000633:toxicity; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays
chemical_list: D014227:Triazines; D000077704:Tirapazamine; D003520:Cyclophosphamide; D010100:Oxygen