Antitumour activity of N6-substituted PMEDAP derivatives against T-cell lymphoma.
The antitumour activity of four N6-substituted PMEDAP derivatives, Me2NEt-PMEDAP, allyl-PMEDAP, Me2-PMEDAP and cypr-PMEDAP, selected on the basis of their in vitro cytostatic activity, was studied in an in vivo model of haematological malignancy of inbred Sprague-Dawley rats. These compounds are believed to serve as the prodrugs of another (phosphonomethoxy)ethyl derivative, PMEG (9-[2-phosphonomethoxy) ethyl] guanine. We compared their toxicity and ability to inhibit tumour development in two different dosage regimes with those of their parent compound PMEDAP, as well with PMEG. The study confirmed the anticancer efficacy of the parental compound PMEDAP. Unlike PMEDAP, its N6-mono- and disubstituted congeners Me2NEt-PMEDAP, allyl-PMEDAP and Me2-PMEDAP were less potent or exhibited the same antineoplastic effect as PMEDAP. cypr-PMEDAP significantly decreased the survival of lymphoma-bearing rats due to high toxicity, which was approximately the same as that of PMEG. Therefore, these acyclic nucleoside phosphonates substituted at the 6-position of 2,6-diaminopurine ring do not seem to be promising drugs for the treatment of haematological malignancies.
Valeriánová
M
M
Institute of Biology and Medical Genetics, 1st Faculty of Medicine and General Teaching Hospital, Charles University, Prague, Czech Republic.
Votruba
I
I
Holy
A
A
Mandys
V
V
Otová
B
B
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001772:Blood Cell Count; D001854:Bone Marrow Cells / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D007621:Karyotyping; D008223:Lymphoma / Q000188:drug therapy; D008297:Male; D008938:Mitosis; D009368:Neoplasm Transplantation; D063065:Organophosphonates / Q000494:pharmacology; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
C433937:9-(2-(phosphonomethoxy)ethyl)-N(6)-(2-dimethylaminoethyl)-2,6-diaminopurine; C433941:9-(2-(phosphonomethoxy)ethyl)-N(6)-allyl-2,6-diaminopurine; C433940:9-(2-(phosphonomethoxy)ethyl)-N(6)-dimethyl-2,6-diaminopurine; D000970:Antineoplastic Agents; C120401:N(6)-cyclopropyl-9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine; D063065:Organophosphonates; D011355:Prodrugs; C059499:9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine; D000225:Adenine