POLYAMINE DEPRIVATION - A NEW TOOL IN CANCER-TREATMENT

The fact that tumors require polyamines for growth has been demonstrat ed in vitro and in vivo and widely reported. This finding led to the u se of polyamine. biosynthetic enzymes as targets for antitumor drug de sign. Highly efficient in vitro selective inhibitors of ornithine deca rboxylase such as DFMO do not produce important antitumoral effects in vivo, due to the ability of tumor cells to uptake extracellular polya mines. A new strategy was developed, combining a systematic blockade o f all endogenous and exogenous sources of polyamines in vivo. Sources of exogenous polyamines were eliminated by administration of a polyami ne-free diet to the animals and decontamination of their gastrointesti nal tract. Important antitumoral effects were obtained with this polya mine deprivation and are presented with two experimental models of tum ors (Lewis lung carcinoma, Mar Lylu prostatic carcinoma). Biological p arameters, modified in cases of cancer, were restored to normal values in, treated animals: blood counts and NK cytotoxic activity. Number o f metastases was significantly reduced. Given that in man cancer treat ment remains unsatisfactory due to incomplete cell kill, development o f resistance to treatment and secondary effects of chemotherapy, we ch ose to investigate the potential interest of polyamine deprivation in this field. By combining clinically applied cytotoxic drugs with polya mine deprivation, we observed an improvement of their antitumoral effi ciency: a considerable retardation of tumor growth paired with a marke d increase in life-span of the treated animals. Our observations confi rm that polyamines absorbed from exogenous sources, mainly food and ga strointestinal tract, play an important role in tumor growth control. Furthermore, the study shows that polyamine deprivation represents an important potential therapeutic tool in improved management of cancer treatment.