The overall objective of this project is to increase the sensitivity of tumors compared to normal tissues to radiotherapy and to chemotherapy. The rationale is two fold: first, that hypoxic cells in some types of human solid tumors limit control rates to radiotherapy and responses to some chemotherapeutic drugs; second (and paradoxically), that tumor hypoxia can be excploited for therapeutic benefit. Our objective under the first rationale is to explore three novel ways to overcome the problem of hypoxic cells (possibly the acutely hypoxic cells) and compare its ability to radiosensitize mouse tumors in multifraction protocols both with other agents that increase tumor oxygenation (Fluosol-DA + carbogen, and the drug bezafibrate), and also with SR 2508, an electron-affinic radiosensitizer. Our second and third means of overcoming the problem of tumor hypoxia involve use of SR 4233, the lead compound in a series of benzotriazine N-oxides, which constitute a newly discovered class of bireductive agents. SR 4233 selectively kills hypoxic tumor cells, and we propose detailed molecular and cellular studies of the mechanism involved. We will also perform studies of its cytotoxicity in mouse tumors and possible means of enhancing this toxicity. SR 4233 also radiosensitizes cells, however, in a novel way; sensitization is prduced by pre- or post-irradiation incubation with the drug. We propose to investigate the mechanism for this and its potential use in multifraction radiotherapy. Vasoactive compounds, such as the antihypertensive drug hydralazine, can increase tumor hypoxia, and this will allow use of SR 4233 both as a cytotoxic and radiosensitizing agent to exploit this tumor-specific induced hypoxia. The clinical potential of this approach, both with and without irradiation, will be investigated in single and multifraction studies with hydralazine and other means of inducing tumor hypoxia. To explore mechanisms, we will use a variety of cellualr and molecular techniques including clonogenic survival with normal and sensitive cells and with cells from different regions of spheroids, alkaline and neutral filter elution, DNA sequencing, and a variety of biochemical assays. The potential clinical applicability will be investigated using fractionated protocols with the EMT6, RIF-1, SCCVII and KHT mouse tumors and the HT 1080 human fibrosrcoma. We will also assay for normal tissue sensitization using skin reactions and lung damage.
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