N,N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine (DPPE; tesmilifene), a chemopotentiating agent with hormetic effects on DNA synthesis in vitro, may improve survival in patients with metastatic breast cancer.
N,N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine (DPPE; tesmilifene) is a novel anti-histaminic and chemopotentiating agent that has a hormetic effect on DNA synthesis in MCF (Michigan Cancer Foundation)-7 human breast cancer cells in vitro and stimulates the growth of experimental tumors in rodents. In a prospectively randomized phase three trial (NCIC MA.19), 152 patients who were co-administered DPPE and doxorubicin survived 50% longer (P < 0.03) than 153 patients who were administered the same dose and schedule of doxorubicin alone. At clinically relevant in vitro concentrations that do not inhibit the P-glycoprotein (P-gp) pump, DPPE selectively sensitizes the cancer cells that express the multiple drug resistance phenotype, making them more susceptible to the cytotoxic effects of chemotherapeutic agents, including anthracyclines and taxanes. Based on its previously demonstrated interaction with histamine at CYP3A4, a P450 that metabolizes arachidonic acid, and its induction of high levels of prostacyclin in the gut of rodents, modulation by DPPE of the intracellular concentration of arachidonate products, such as hydroxyeicosatetraeinoic acids, implicated in increased cancer cell proliferation and metastasis, is postulated.
Brandes
Lorne J
LJ
Department of Medicine and Pharmacology/Therapeutics, University of Manitoba and Section of Hematology/Oncology, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg MB R3E0V9, Canada. brandes@cc.umanitoba.ca
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000277:Adjuvants, Pharmaceutic / Q000627:therapeutic use*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017326:Clinical Trials, Phase III as Topic; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D010647:Phenyl Ethers / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D000277:Adjuvants, Pharmaceutic; D004273:DNA, Neoplasm; D010647:Phenyl Ethers; D010975:Platelet Aggregation Inhibitors; C043062:tesmilifene