Antisense inhibition of methylenetetrahydrofolate reductase reduces cancer cell survival in vitro and tumor growth in vivo.
OBJECTIVE
Many cancer lines are methionine dependent and decrease proliferation when methionine supply is limited. Methylenetetrahydrofolate reductase (MTHFR) generates the folate derivative for homocysteine remethylation to methionine. We investigated the effect of antisense-mediated inhibition of MTHFR on survival of human cancer cells.


METHODS
We examined the in vitro and in vivo anticancer effects of a combination of MTHFR antisense and standard cytotoxic drugs.


RESULTS
Specific antisense against MTHFR (EX5) showed significant inhibitory effects on growth of human colon, lung, breast, prostate, and neuroblastoma tumor cells in vitro compared with that of the control oligonucleotide. Cytotoxic drugs (5-fluorouracil, cisplatin, or paclitaxel) potentiated the effect of EX5. In vivo, antisense alone or in combination with cytotoxic drugs inhibited the growth of human colon and lung carcinoma xenografts. In comparison with control oligonucleotide, treatment with EX5 inhibited growth of colon tumors and lung tumors by 60% and 45%, respectively. EX5 with 5-fluorouracil decreased growth of colon tumors by an additional 30% compared with EX5 alone, and EX5 with cisplatin decreased growth of lung tumors by an additional 40% compared with cisplatin alone. Growth inhibition by EX5 was associated with decreased amounts of MTHFR protein and with increased amounts of an apoptosis marker.


CONCLUSIONS
Our results confirm that MTHFR inhibition decreases tumor growth and suggest that inhibition of MTHFR by antisense or small molecules may be a novel anticancer approach.
Stankova
Jitka
J
Departments of Human Genetics, Pediatrics and Biology, Research Institute, McGill University-Montreal Children's Hospital, 4060 Saint Catherine Street West, Montreal, Quebec, Canada H3Z 2Z3.
Shang
Jijun
J
Rozen
Rima
R
D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology*; D049109:Cell Proliferation; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000473:pathology*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D009447:Neuroblastoma / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D002945:Cisplatin