Tumor microenvironment and the response to anticancer therapy.
Human solid tumors are invariably less well oxygenated than normal tissues. This leads to resistance to radiotherapy and anticancer chemotherapy, as well as predisposing for increased tumor metastases. Prolonged hypoxia of the tumor tissue also leads to necrosis, and necrotic regions are also characteristic of solid tumors. These two characteristics-hypoxia and necrosis-represent clear differences between tumors and normal tissues and are potentially exploitable in cancer treatment. This review focuses on the phenomenon of tumor hypoxia and how hypoxia and its accompanying necrosis can be exploited in therapy. One such strategy is to use drugs that are toxic only under hypoxic conditions, and the first drug of this class to enter clinical testing, tirapazamine, is showing considerable promise. The second way to exploit hypoxia is to take advantage of the selective induction under hypoxia of the transcription factor HIF-1 (hypoxia-inducible factor 1). Gene therapy strategies based on this are in development. Finally, tumor hypoxia can be exploited using live obligate anaerobes that have been genetically engineered to express enzymes that can activate non-toxic prodrugs into toxic chemotherapeutic agents.
Brown
J Martin
JM
CCSR 1255, Division of Radiation and Cancer Biology, Dept. of Radiation Oncology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA 94305, USA. mbrown@stanford.edu
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015687:Cell Hypoxia / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008954:Models, Biological; D009336:Necrosis; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D000077704:Tirapazamine; D014157:Transcription Factors / Q000378:metabolism*; D014227:Triazines / Q000627:therapeutic use / Q000633:toxicity
D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011838:Radiation-Sensitizing Agents; D014157:Transcription Factors; D014227:Triazines; D000077704:Tirapazamine