POLYAMINE MODULATION OF SQUAMOUS CANCER GROWTH KINETICS

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Radiation is a primary treatment modality for squamous cell carcinomas (SCCs) of the head and neck (H&N) region (ie, tongue, pharynx, larynx). Laboratory and clinical data now indicate that proliferation of surviving tumor clonogens during a conventional 7-9 week course of curative H&N radiotherapy compromises tumor control due to rapid repopulation of tumor clonogens during treatment. Tumor kinetic analysis via flow cytometry confirms that clonogenic doubling times for SCCs of the H&N are among the most rapid of human solid tumors with median potential doubling times (Tpot) of 4-5 days. Intensified radiotherapy fractionation schedules delivered over a reduced overall treatment time provide one method of approach to counteract this tumor clonogen repopulation issue. Several such accelerated treatment regimens are being successfully employed in h&N cancer patients worldwide with improved locoregional tumor control rates, but with markedly increased acute treatment toxicities. An alternative biological method of approach to the rapid clonogen repopulation issue involves the manipulation of tumor growth kinetics during the radiotherapy treatment course, rather than the intensification of physical radiation treatment parameters. The objective of this proposal is therefore to investigate the capacity of antiproliferative agents involved in polyamine metabolism to slow tumor growth kinetics in human SCCs of the H&N. Specific agents for study include the polyamine biosynthesis inhibitor alpha-difluoromethylornithine (DFMO), and the newly synthesized polyamine analogs 1,19-bix-(ethylamino)-5,10,15- traiazanonadecane (BE-4-4-4-4) and N,N-bis[3-(ethylamino)propyl]-1,7- hepatanediamine (BE-3-7-3). It is hypothesized that these polyamine pathway metabolic inhibitors, with the capacity to decrease tumor proliferation rate during a course of curative radiotherapy, will provide a method whereby improved tumor control rates can be achieved in rapidly dividing SCCs of the H&N. A series of in vitro flow cytometry kinetic studies, in vivo mouse xenograft growth studies, and normal mucosal tissue response studies will be performed to examine the role that polyamine modulation of tumor proliferation kinetics might play in influencing the ultimate radiocurability of human SCCs.