Similarity of serum-tumor pharmacokinetics of antitumor agents in man and nude mice.
A pharmacokinetic comparison was made between nude mice and human gastric cancer patients. This comparison is important in order to optimize the human tumor xenograft-nude mouse system as a screening panel for potential antitumor agents. In this report, mitomycin C (MMC), doxorubicin (DXR), 5-fluorouracil (5-FU) and cisplatin (DDP) were administered to nude mice bearing human tumor subcutaneous xenografts in maximum tolerated doses and to patients with gastric cancer at conventional doses. The concentrations of antitumor agents in serum and tumor were detected by bioassay for MMC and 5-FU, by high performance liquid chromatography for DXR, and by atomic absorption method for DDP. Peak drug concentrations in the serum (Cmax) the mice and humans correlated well with statistical significance (R = 0.999, P < 0.0001). When Cmax and drug concentrations in the tumor (T) the mice and human were compared with each other to evaluate the uptake of drugs into the tumor from the serum and calculated as T/Cmax, similar results were observed for the same agent with statistical significance (r = 0.990, p < 0.02). These results indicate that the human tumor xenograft-nude mouse system and humans are essentially similar pharmacodynamically, which further validates the uses of this system to evaluate potential antitumor agents.
Kubota
T
T
Department of Surgery, School of Medicine, Keio University, Tokyo, Japan.
Inoue
S
S
Furukawa
T
T
Ishibiki
K
K
Kitajima
M
M
Kawamura
E
E
Hoffman
R M
RM
D000328:Adult; D000368:Aged; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D002945:Cisplatin / Q000097:blood / Q000493:pharmacokinetics*; D004317:Doxorubicin / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005472:Fluorouracil / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D016685:Mitomycin / Q000097:blood / Q000493:pharmacokinetics*; D012044:Regression Analysis; D013274:Stomach Neoplasms / Q000378:metabolism*; D014183:Transplantation, Heterologous
D016685:Mitomycin; D004317:Doxorubicin; D002945:Cisplatin; D005472:Fluorouracil