Interactions of various nitroheterocyclic radiation sensitizers with cancer chemotherapeutic agents and radiation used in combination will be studied in an in vivo lung tumor model. Experiments are proposed to determine the effect on tumor cells growing in the lung of adding a sensitizer to a protocol combining the nitrosourea CCNU with localized radiation or the alkylating chemotherapeutic agent cyclophosphamide. Treatment efficacy will be assessed using endpoints of clonogenic cell survival, tumor regrowth delay and tumor-free animal survival. The influence that the inclusion of a sensitizer in such protocols has on secondary ovarian and renal metastases arising from lung tumors also will be established. Both the incidence of metastases to the ovaries and kidneys and their response to the treatment regimen will be measured. The nature of the interaction between such combined modality therapies will be determined through isoeffect plot (isobologram) analysis. It also is our objective to elucidate the role of pharmacokinetic changes (using HPLC analysis) in the combined modality protocols. The potential therapeutic benefit which may be achieved through the addition of a sensitizer to the different treatment regimen will be determined by measuring tumor responses as well as the early and late effects on critical normal tissues. Both tumor and normal tissue responses also will be studied under conditions where sensitizers are administered such that sensitizer pharmacokinetics achievable in human plasma are mimicked. Those treatment protocols giving rise to the largest therapeutic gains will be evaluated in xenografts of human lung cancer. These investigations should yield information which will improve our understanding of combined modality therapies and may guide the efforts for the most effective use of combinations of sensitizers, chemotherapeutic agents and radiation.
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