Clinical-translational strategies for the elevation of Nm23-H1 metastasis suppressor gene expression.
Interruption of the tumor metastatic process is a new, thought provoking molecular target for the treatment of cancer. The Nm23-H1 metastasis suppressor gene stands as a validated molecular target owing to its reduced expression in many aggressive human tumors, and the reduction in metastatic potential in vivo upon re-expression in multiple cell lines. Several compounds have been identified which elevate Nm23-H1 expression in vitro including indomethacin, gamma Linolenic Acid, trichostatin A, 5-aza-deoxycytidine, and high dose medroxyprogesterone acetate. Using a model of lung metastatic colonization by MDA-MB-231 human breast carcinoma cells, we demonstrated that high dose MPA reduced the formation of overt lung metastases by 37-46% and those metastases that formed were statistically smaller. A Phase II clinical trial of high dose MPA, alone or in combination with metronomic chemotherapy has recently opened.
Marshall
Jean-Claude
JC
Women's Cancers Section, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. marshallje@mail.nih.gov
Lee
Jong Heun
JH
Steeg
Patricia S
PS
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016147:Genes, Tumor Suppressor / Q000187:drug effects*; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000627:therapeutic use*; D051379:Mice; D054778:NM23 Nucleoside Diphosphate Kinases; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
D018931:Antineoplastic Agents, Hormonal; D054778:NM23 Nucleoside Diphosphate Kinases; D011965:Receptors, Glucocorticoid; D017258:Medroxyprogesterone Acetate