PNEUMOCYSTIS CARINII POLYAMINE METABOLISM

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DESCRIPTION: (Adapted from applicant's abstract). Pneumocystis carinii pneumonia (PCP) affects over 50% of patients with AIDS. DL-alpha-difluoromethylornithine (DFMO, eflornithine), an inhibitor of one key enzyme of polyamine biosynthesis, has been used as an alternative treatment for PCP. While DFMO is less toxic than most PCP therapies, efficacy is also lower so that it is not currently considered as a therapy for this disease. New tools have been developed in this laboratory for studies of P. carinii and for studies of polyamine metabolism. Interpretation of data collected with these tools led to the hypothesis that one reason DFMO is selectively toxic to P. carinii is that, unlike mammalian cells, P. carinii does not regulate polyamine catabolism. Another interpretation led to the prediction that DFMO would be most effective when administered as a continuos infusion, a prediction confirmed in an animal model. Further information on P. carinii polyamine metabolism can be expected to lead to new improvements including identification of other metabolic targets within polyamine metabolism. The following studies will be performed. The mechanism of DFMO-induced rapid polyamine depletion will be determined by studying excretion of polyamines and by characterizing the catabolic and salvage enzymes spermidine/spermine acetyl transferase (SSAT) and polyamine oxidase (PAO), respectively. The dynamics of P. carinii polyamine metabolism will be studied with emphasis on the relative importance of de novo polyamine biosynthesis vs scavenge of polyamines from the host. Polyamine transporter (s) and biosynthetic enzymes will be characterized. A panel of compounds which have been shown to modulate polyamine metabolism in other cells will be used as probes of P. carinii polyamine metabolism. These compounds will also be studied for their ability to manipulate polyamine transport and metabolism as well as for their ability to inhibit P. carinii growth in vitro.