Combination therapy with 2-difluoromethylornithine and a polyamine transport inhibitor against murine squamous cell carcinoma.
Using a recently developed autochthonous mouse model of squamous cell carcinoma (SCC), a combination therapy targeting polyamine metabolism was evaluated. The therapy combined 2-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (ODC), and MQT 1426, a polyamine transport inhibitor. In 1 trial lasting 4 weeks, combination therapy with 0.5% DFMO (orally, in the drinking water) and MQT 1426 (50 mg/kg i.p., bid) was significantly more effective than with either single agent alone when complete tumor response was the endpoint. In the combination group, 72% of SCCs responded completely vs. 21 and 0% for DFMO and MQT 1426, respectively. A second trial involved a 4-week treatment period followed by 6 weeks off-treatment. With apparent cures as an endpoint, combination therapy was again more effective than either agent alone: a 50% apparent cure rate was observed in the combination group vs. 7.7% in the DFMO group. MQT 1426 had no inhibitory effect on SCC ODC activity nor did it enhance the inhibition by DFMO, but SCC polyamine levels declined more rapidly when treated with combination therapy vs. DFMO alone. The apoptotic index in SCCs was transiently increased by combination therapy but not by DFMO alone. Thus, targeting both polyamine biosynthesis and polyamine transport from the tumor microenvironment enhances the efficacy of polyamine-based therapy in this mouse model of SCC.
Chen
Yan
Y
Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.
Weeks
Reitha S
RS
Burns
Mark R
MR
Boorman
David W
DW
Klein-Szanto
Andres
A
O'Brien
Thomas G
TG
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D000518:Eflornithine / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism* / Q000493:pharmacokinetics*; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; C509826:MQT 1426; D011073:Polyamines; D013096:Spermine; D009955:Ornithine Decarboxylase; D000518:Eflornithine