Combination therapy with 5-fluorouracil and L-canavanine: in vitro and in vivo studies.
L-Canavanine (CAV) is a potent L-arginine antagonist, produced by legumes such as the jack bean, Canavalia ensiformis. CAV is cytotoxic to MIA PaCa-2 human pancreatic cancer cells. We sought to determine whether CAV's efficacy as an anticancer agent might be increased in combination with 5-fluorouracil (5-FU), a pyrimidine antimetabolite with activity against solid tumors. Using optimal conditions for the expression of CAV's cytotoxicity against MIA PaCa-2 cells, CAV was more cytotoxic to the cells than 5-FU. The combination of both drugs at a fixed molar ratio of 1:1 exhibited synergistic effects in the cells as determined by combination index analysis. The combination of 5-FU:CAV was tested at a ratio of 5:1 and exhibited antagonism at lower effect levels, additivity at 50% effect levels and slight synergism at higher effect levels. A 10:1 combination of both drugs (5-FU:CAV) exhibited antagonistic effects at all levels. When the drugs were combined at a molar ratio of 20:1, increased antagonism was observed. When CAV (1.0 or 2.0 g/kg daily) and/or 5-FU (35 mg/kg daily) was administered to colonic tumor-bearing rats for five consecutive days, the antitumor activity of the drug combination was significantly greater than the combined effects of either drug alone. However, the body weight loss experienced by CAV-treated rats was increased in those rats exposed to a combination of both drugs. These studies using different tumors provide in vitro and in vivo evidence that combination therapy offers a viable means of improving CAV's intrinsic efficacy while decreasing the concentration of 5-FU required to produce the same cytotoxic effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Swaffar
D S
DS
Division of Pharmacology and Toxicology, School of Pharmacy, Northeast Louisiana University, Monroe 71209, USA.
Ang
C Y
CY
Desai
P B
PB
Rosenthal
G A
GA
Thomas
D A
DA
Crooks
P A
PA
John
W J
WJ
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use*; D002172:Canavanine / Q000008:administration & dosage; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007887:Fabaceae / Q000737:chemistry; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms; D010946:Plants, Medicinal; D051381:Rats; D011916:Rats, Inbred F344; D014407:Tumor Cells, Cultured
D002172:Canavanine; D005472:Fluorouracil