Potent differentiation-inducing properties of the antiretroviral agent 9-(2-phosphonylmethoxyethyl) adenine (PMEA) in the rat choriocarcinoma (RCHO) tumor cell model.
9-(2-phosphonylmethoxyethyl)adenine (PMEA) and its closely related structural analogue (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) are potent inhibitors of retroviruses and hepatitis B virus. In its oral prodrug form (adefovir dipivoxil), PMEA is currently the subject of advanced phase II/III clinical trials for the treatment of HIV infections. PMEA has also been shown to be a potent differentiation-inducing agent. In the present study, PMEA was found to have a strong differentiation-inducing effect on rat choriocarcinoma (RCHO) cells, comparable to that of methotrexate, which is the drug of choice for the chemotherapy of choriocarcinoma in humans. PMEA induced differentiation of choriocarcinoma trophoblast cells in a concentration-dependent manner within the 2- to 50-microM concentration range, as ascertained by giant cell formation, alkaline phosphatase induction, progesterone secretion, and the disappearance of a cytotrophoblast-specific surface antigen. PMEA had to be exposed to the rat choriocarcinoma cell cultures for at least 2-3 days to achieve optimal growth inhibition and differentiation of the tumor cells. Unlike PMEA, (R)-9-(2-phosphonylmethoxypropyl)adenine failed to induce differentiation of proliferating cytotrophoblasts into nonproliferating, hormonally active giant cells. This points to the specificity of PMEA as an inducer of choriocarcinoma cell differentiation.
Hatse
S
S
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Naesens
L
L
De Clercq
E
E
Balzarini
J
J
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis; D000954:Antigens, Surface / Q000096:biosynthesis / Q000187:drug effects; D000998:Antiviral Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002822:Choriocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004359:Drug Therapy, Combination; D004790:Enzyme Induction / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008727:Methotrexate / Q000494:pharmacology; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011374:Progesterone / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D012190:Retroviridae / Q000187:drug effects*; D000068698:Tenofovir; D014327:Trophoblasts / Q000187:drug effects / Q000473:pathology; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D000998:Antiviral Agents; D006131:Growth Inhibitors; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011374:Progesterone; C053001:adefovir; D000068698:Tenofovir; D000469:Alkaline Phosphatase; D000225:Adenine; D008727:Methotrexate