Synergistic interaction between etoposide and 1-beta-D-arabinofuranosylcytosine.
The sequence-dependency of the antitumor effect of etoposide (VP-16) and 1-beta-D-arabinofuranosylcytosine (ara-C) and its mechanisms were investigated in L1210 ascites tumor. Treatment with VP-16 (15 mg/kg) and ara-C (25 mg/kg) was administered intraperitoneally on days 1, 4, and 7 after tumor inoculation. Three-hour pretreatment with VP-16 followed by ara-C produced 70% of cure rate, but only 20% of cure rate was obtained with the reverse sequence. Simultaneous administration led to the worst therapeutic result. To clarify this sequence-dependent interaction of the both drugs, the effect of VP-16 on incorporation of ara-C into DNA was investigated in vivo. On day 3 after intraperitoneal transplantation of 1 x 10(6) L1210 cells, 15 mg/kg of VP-16 and 1 microCi of (3H)ara-C was administered intraperitoneally with or without time interval. The effect of VP-16 on ara-C incorporation was also strikingly schedule-dependent and compatible with the schedule dependency of the antitumor effect. At 1 hr after injection of ara-C, simultaneous administration of 15 mg/kg of VP-16 reduced ara-C incorporation by 67% of ara-C injection alone. But in sharp contrast to simultaneous-administration, 3 hour preadministration of VP-16 increased ara-C incorporation up to 247%. From 1 to 6 hour after intraperitoneal administration of 15 mg/kg of VP-16, the sedimentation rate of L1210 DNA was increasing on alkaline sucrose gradients. This repairing period from VP-16 induced DNA damage might be the vulnerable time to ara-C through an increase in ara-C incorporation into DNA.
Ohkubo
T
T
Department of Pediatrics, Mie University, School of Medicine, Japan.
Hori
H
H
Higashigawa
M
M
Kawasaki
H
H
Kamiya
H
H
Sakurai
M
M
Kagawa
Y
Y
Kakito
E
E
Sumida
K
K
Ooi
K
K
D000818:Animals; D003561:Cytarabine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D013997:Time Factors
D004273:DNA, Neoplasm; D003561:Cytarabine; D005047:Etoposide