Polyamine deprivation: a new tool in cancer treatment.
The fact that tumors require polyamines for growth has been demonstrated in vitro and in vivo and widely reported. This finding led to the use of polyamine biosynthetic enzymes as targets for antitumor drug design. Highly efficient in vitro selective inhibitors of ornithine decarboxylase such as DFMO do not produce important antitumoral effects in vivo, due to the ability of tumor cells to uptake extracellular polyamines. A new strategy was developed, combining a systematic blockade of all endogenous and exogenous sources of polyamines in vivo. Sources of exogenous polyamines were eliminated by administration of a polyamine-free diet to the animals and decontamination of their gastrointestinal tract. Important antitumoral effects were obtained with this polyamine deprivation and are presented with two experimental models of tumors (Lewis lung carcinoma, Mat Lylu prostatic carcinoma). Biological parameters, modified in cases of cancer, were restored to normal values in treated animals: blood counts and NK cytotoxic activity. Number of metastases was significantly reduced. Given that in man cancer treatment remains unsatisfactory due to incomplete cell kill, development of resistance to treatment and secondary effects of chemotherapy, we chose to investigate the potential interest of polyamine deprivation in this field. By combining clinically applied cytotoxic drugs with polyamine deprivation, we observed an improvement of their antitumoral efficiency: a considerable retardation of tumor growth paired with a marked increase in life-span of the treated animals. Our observations confirm that polyamines absorbed from exogenous sources, mainly food and gastrointestinal 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.
Quemener
V
V
Laboratoire de Biologie Cellulaire, Centre Hospitalier-Universitaire de Rennes, France.
Blanchard
Y
Y
Chamaillard
L
L
Havouis
R
R
Cipolla
B
B
Moulinoux
J P
JP
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003520:Cyclophosphamide / Q000627:therapeutic use; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004032:Diet; D004305:Dose-Response Relationship, Drug; D006867:Hydrolases / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011073:Polyamines / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051381:Rats; D011919:Rats, Inbred Strains; D013154:Spleen / Q000187:drug effects / Q000378:metabolism
D011073:Polyamines; D003520:Cyclophosphamide; D006867:Hydrolases