Theoretical considerations and in vitro concentration response studies with two human colorectal carcinoma cell lines. The rational experimental base for clinical studies in regional chemotherapy.
The theoretical advantage of regional vs. systemic chemotherapy was calculated, based on pharmacokinetic considerations. The relevance of exposure time and high local concentrations of chemotherapeutic drugs for regional chemotherapy was elucidated in time dependent concentration response curves with two human cell lines. The theoretical pharmacological advantage of regional vs. systemic chemotherapy was defined by the formula Rd = (AUCi. a. 1 + AUCi. a. 2)/(AUCi. v.) and in hepatic artery infusion is for adriamycin (ADM) 5.8-.6, cis-platinum (CDDP) 8, epirubicine (EPI) 6.3, 5-fluorouracil (5-FU) 22-58, mitomycin C (MMC) 4.6, mitoxantrone (NOV) 6.3. All drugs but 5-FUDR exerted concentration response behaviour in the cell line-experiments. In the cell lines cytotoxicity depended on exposure time so that concentration chi time products at (IC50), (c chi t (IC50)), were calculated to determine an optimal in vitro exposure time. Based on these results and clinical considerations, optimal clinical exposure times could be defined for regional chemotherapy. The results may be of high relevance for e.g. hepatic artery infusion at the lower and chemoembolization or intraperitoneal instillation at the higher test concentration, respectively.
Leder
G H
GH
Dept. of General and Visceral Surgery, University of Ulm, Germany.
Pillasch
J
J
Kornmann
M
M
Danenberg
P V
PV
Link
K H
KH
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000097:blood; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000097:blood; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000097:blood; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage / Q000097:blood; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage / Q000097:blood; D015251:Epirubicin / Q000008:administration & dosage / Q000097:blood; D005467:Floxuridine / Q000008:administration & dosage / Q000097:blood; D005472:Fluorouracil / Q000008:administration & dosage / Q000097:blood; D006499:Hepatic Artery; D006801:Humans; D007261:Infusions, Intra-Arterial; D008558:Melphalan / Q000008:administration & dosage / Q000097:blood; D016685:Mitomycin / Q000008:administration & dosage / Q000097:blood; D008942:Mitoxantrone / Q000008:administration & dosage / Q000097:blood; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D005467:Floxuridine; D015251:Epirubicin; D016685:Mitomycin; D004317:Doxorubicin; D008942:Mitoxantrone; D002945:Cisplatin; D008558:Melphalan; D005472:Fluorouracil