Hyperthermia, hypoxia and chemotherapy: New interactions and perspectives

Tumour hypoxia is a crucial factor in oncology, since it contributes to tumour progression by the activation of genes associated with those promoting angiogenesis and stopping apoptosis. Moreover it has profound effects on therapy: oxygen helps to stabilise radiation and chemotherapeutic damage in DNA, while hypoxic cells show considerable resistance to chemo-radiotherapy; this is considered the major cause for the failure of therapy in some tumours. Attempts to overcome this effect include the use of hyperthermia, oxygen-mimetic "radiosensitizers" and multifractional radiotherapy to allow re-oxygenation of tumour tissue. To achieve greater efficacy many researchers are attempting to amplify the differences between normal and malignant cells at the cellular milieu as well as their biomolecular properties. Preclinical thermochemotherapy studies have given valuable information on the schedule of the cytotoxic interaction between the different agents and on the molecular mechanisms responsible for the potentiating effect. Several studies have demonstrated that the cytotoxic activity of various chemotherapeutic agents is enhanced by mild or moderate hyperthermia (40.5-43°C). There are data regarding doxorubicin, the platinum compounds cisplatin, carboplatin and oxaliplatin, the bifunctional alkylating agent melphalan and the antimetabolite methotrexate, gemcitabine, docetaxel and taxol which indicate that in each case the maximal cytotoxicity occurs when the drug is administered simultaneously with hyperthermia. Adenovirus-mediated and heat-activated gene therapy provides a novel approach to radiosensitize human tumours. Tumour hypoxia is a unique target for hyperthermia and cancer bioreductive therapy that could be exploited for therapeutic use.