ANTI TOPOISOMERASE I AEROSOLS FOR LUNG CANCER THERAPY

The plant alkaloid camptothecin (CPT) has shown significant anti-topoisomerase I and antitumor activity against a wide variety of human tumors xenografted in nude mice. In recent studies conducted by Dr. Knight, professor and chair of the Department of Physiology of the Baylor University College of Medicine, the administration of dilauroylphosphatidylcholine (DLPC) liposome aerosols containing 9-nitrocamptothecin (9-NC) have been shown to very effectively inhibit the growth of human breast, colon and lung cancer xenografts. However, recent results for the laboratory of Dr. Burke at the University of Kentucky presented at the 2001 AACR and ASCO meetings indicate that translation of this very promising aerosol therapy to the clinic will be very difficult to achieve. Clinically-relevant camptothecins such at 9-NC contain a lactone ring pharmacophore which is essential for activity, but these drugs hydrolyze rapidly in human tissue and blood. Human serum albumin (HSA) avidly binds the ring-opened form of 9-NC and shifts the equilibrium such that virtually all of the active form of 9-NC disappears in human blood and tissue. This effect is very specific for human serum albumin, with the active lactone levels of 9-NC being some 100-times higher in mouse blood versus human blood which provides a basis for the favorable therapeutic outcomes obtained in the xenograft models in nude mice. Thus a real need exists for the development of camptothecins that exhibit high lactone stability in human blood and tissues. Towards this end, the Burke and Curran labs of the University of Kentucky and University of Pittsburgh, respectively, have developed novel, potent and highly tissue-stable camptothecins known as silatecans and homosilatecans. DB-67 is the lead silatecan which has been shown to effectively cure mice of intracranial U87 human glioma xenografts. Through the RAID Program of the National Cancer Institute, the Burke lab is currently generating the necessary data that will fulfill the requirements for a FDA Investigational New Drug application for DB-67 by the end of2001. These efforts include GMP scale up ofDB-67, formulation production, and FDA IND directed toxicology and pharmacology studies. In the current proposal, we intend to create aerosol formulations of our most promising silatecan and homosilatecan agents. We intend to work with Dr. Chen to optimize this important new anti-topoisomerase I therapy for lung cancer. The pharmacokinetics and efficacy of inhaled silatecans and homosilatecans forumulated in DLPC liposomes will be evaluated. C57BL/6 mice with subcataneous Lewis lung carcinoma, Swiss nu/nu mice with human lung carcinoma xenografts will be studied.