title: 9-(2-phosphonylmethoxyethyl)-N6-cyclopropyl-2,6-diaminopurine: a novel prodrug of 9-(2-phosphonylmethoxyethyl)guanine with improved antitumor efficacy and selectivity in choriocarcinoma-bearing rats.
abstract: The novel acyclic nucleoside phosphonate analogue 9-(2-phosphonylmethoxyethyl)-N6-cyclopropyl-2,6-diaminopurine (cPr-PMEDAP) was shown in vitro to act as an intracellular prodrug of 9-(2-phosphonylmethoxyethyl)guanine (PMEG). We compared the in vivo antitumor efficacy and selectivity of cPr-PMEDAP, its progenitor PMEDAP, and PMEG in a rat choriocarcinoma tumor model. The rats, inoculated with rat choriocarcinoma (RCHO) cells under the renal capsule, were treated IP during 10 days. Macroscopical and histological examination of the RCHO-inoculated kidneys was performed at two time points (i.e., immediately after the end of treatment or after an additional drug-free period of 2 weeks). Complete inhibition of choriocarcinoma tumor development was achieved upon treatment with cPr-PMEDAP, PMEG, and PMEDAP at a daily dose of 10, 1, and 50 mg/kg, respectively. At these doses, all three compounds produced moderate to strong toxicity (evidenced by atrophy of lymphoid organs and reduced body weight gain). When compared at the maximum tolerated (sublethal) doses (i.e., 0.5, 10, and 50 mg/kg for PMEG, cPr-PMEDAP, and PMEDAP, respectively), cPr-PMEDAP proved superior to PMEG and PMEDAP in achieving a complete inhibition of tumor development. Also, whereas PMEG was unable to produce a prolonged antitumor effect, the animals treated with cPr-PMEDAP still showed prominent inhibition of tumor development when tumor size was evaluated at 2 weeks after end of treatment. Based on its efficacy and therapeutic safety, cPr-PMEDAP can be regarded as a promising antitumor agent, which merits further in vivo evaluation in additional tumor models for human neoplasms.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. lieve.naesens@rega.kuleuven.ac.be
authors.forename: L
authors.initials: L
authors.lastname: Naesens
authors.forename: S
authors.initials: S
authors.lastname: Hatse
authors.forename: C
authors.initials: C
authors.lastname: Segers
authors.forename: E
authors.initials: E
authors.lastname: Verbeken
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: M
authors.initials: M
authors.lastname: Waer
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002822:Choriocarcinoma / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D008297:Male; D063065:Organophosphonates / Q000627:therapeutic use*; D009943:Organophosphorus Compounds / Q000627:therapeutic use* / Q000633:toxicity; D011247:Pregnancy; D011355:Prodrugs / Q000627:therapeutic use*; D051381:Rats; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; C120401:N(6)-cyclopropyl-9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011355:Prodrugs; C063380:9-((2-phosphonylmethoxy)ethyl)guanine; C059499:9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine; D006147:Guanine; D000225:Adenine