Benefits of complete polyamine deprivation in hormone responsive and hormone resistant MCF-7 human breast adenocarcinoma in vivo.
Polyamines are ubiquitous cellular compounds which are required for estradiol induced proliferation in breast cancer. Complete polyamine deprivation, using 2 alpha-difluoromethyl-ornithine (DFMO, Eflornithine), a specific inactivator of ornithine decarboxylase (key-enzyme of the polyamine biosynthesis) combined with inhibition of the bacterial production of gastrointestinal polyamine and a polyamine free regimen, was demonstrated to exhibit a cytostatic effect and a decrease of the three tumoral polyamine concentrations in a MCF-7 tumor model. In this experiment, complete polyamine deprivation has been tested on a standard MCF-7 tumor and on a variant MCF-7 tumor (i.e. with a tamoxifen acquired resistance). Polyamine deprivation was effective on the tumor growth, both on standard and variant sub-types. The polyamine contents of two types of tumor were similar, and identically, polyamine deprivation has caused a decrease of putrescine, spermidine and also spermine tumoral concentrations measured by the HPLC method in standard and variant MCF-7 tumors. Acquired tamoxifen resistance is common in patients undergoing hormonal therapy for advanced breast cancer. It has been hypothesized that the direct stimulation of polyamine pathway without estradiol involvement could be one of the mechanisms responsible for the tamoxifen resistance. The ability of polyamine deprivation to inhibit the growth of tumors becoming tamoxifen resistant could offer a therapeutic advantage in case of tumor with acquired tamoxifen resistance and could be tested to prevent or delay the hormonal responsiveness to breast cancer.
Leveque
J
J
Groupe de Recherche En Thérapeutique Anti-Cancéreuse, UPRES-A CNRS 6027, Faculté de Médecine, Rennes, France. levequej@sunaimed.univ-rennes1.fr
Foucher
F
F
Havouis
R
R
Desury
D
D
Grall
J Y
JY
Moulinoux
J P
JP
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D000518:Eflornithine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D004967:Estrogens; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism*; D011700:Putrescine / Q000502:physiology; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology; D013095:Spermidine / Q000502:physiology; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000637:transplantation
D018931:Antineoplastic Agents, Hormonal; D004791:Enzyme Inhibitors; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D009363:Neoplasm Proteins; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D011960:Receptors, Estrogen; D013629:Tamoxifen; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine