Antitumor activity and pharmacology of 1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate: an orally active derivative of 1-beta-D-arabinofuranosylcytosine.
The antitumor activity of 1-beta-D-arabinofuranosylcytosine-5'-alkylphosphates (CnPCAs) against L1210 leukemia in mice after oral administration was demonstrated. The optimum length of the alkyl group on the phosphate moiety of CnPCA for exhibiting a high antitumor activity was found to be between tetradecyl (C14) and tricosyl (C23). The most active alkyl derivative in this system was found to be 1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate (C18PCA). The optimum and minimum effective doses of C18PCA were 100 and 6.25 mg/kg/day (q1d, day 1 to day 5), respectively. The maximum T/C% of C18PCA was approximately 220. The antitumor activity of C18PCA was not greatly dependent on the treatment schedule and route. Plasma concentration of 1-beta-D-arabinofuranosylcytosine (ara-C) remained in the range of 0.4 to 0.75 nmol/ml [corrected] for 24 h after oral administration of 100 mg/kg (170 mumol/kg) of C18PCA. These results indicate that C18PCA administered per orally is absorbed intact through the gastrointestinal tract and area-C is released of long period of time. C18PCA is regarded as an orally active depot form of ara-C.
Kodama
K
K
Research Laboratories, Yamasa Shoyu Co., Ltd., Chiba.
Morozumi
M
M
Saitoh
K
K
Kuninaka
A
A
Yoshino
H
H
Saneyoshi
M
M
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001088:Arabinonucleotides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003561:Cytarabine / Q000493:pharmacokinetics / Q000627:therapeutic use; D003568:Cytidine Monophosphate / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000031:analogs & derivatives; D003597:Cytosine Nucleotides / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D007939:Leukemia L1210 / Q000188:drug therapy*; D008657:Metabolic Clearance Rate; D051379:Mice; D012995:Solubility; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001088:Arabinonucleotides; D003597:Cytosine Nucleotides; D003561:Cytarabine; C061162:1-arabinofuranosylcytosine-5'-stearylphosphate; D003568:Cytidine Monophosphate