Preclinical investigation of tolerance and antitumour activity of new fluorodeoxyglucose-coupled chlorambucil alkylating agents.
Our strategy is to increase drug accumulation in target tumour cells using specific "vectors" tailored to neoplastic tissue characteristics, which ideally are not found in healthy tissues. The aim of this work was to use 2-fluoro-2-deoxyglucose (FDG) as a drug carrier, in view of its well-known accumulation by most primary and disseminated human tumours. We had previously selected two FDG-cytotoxic conjugates of chlorambucil (CLB), i.e. compounds 21a and 40a, on the basis of their in vitro profiles. Here we investigated the antitumour profile and tolerance of these compounds in vitro and in vivo in two murine cell lines of solid tumours. In vitro, we found that micromolar concentrations of compounds 21a and 40a inhibited proliferation of B16F0 and CT-26 cell lines. Interestingly, compounds 21a and 40a were found to act at different levels in the cell cycle: S and subG1 accumulation for 21a and G2 accumulation for 40a. In vivo, a single-dose-finding study to select the Maximum Tolerated Dose (MTD) by the intraperitoneal route (IP) showed that the two peracetylated glucoconjugates of CLB were less toxic than CLB itself. When given to tumour-bearing mice (melanoma and colon carcinoma models), according to a "q4d × 3" schedule (i.e., three doses at 4-day intervals) both compounds demonstrated a promising antitumour activity, with Log Cell Kill (LCK) values higher than 1.3 in both B16F0 and CT-26 models. Hence compounds 21a and 40a are good candidates for further works to develop new highly active antineoplastic compounds.
Miot-Noirault
Elisabeth
E
Clermont Université, Université d'Auvergne, BP 10448, F-63000 Clermont-Ferrand, - Inserm U 990, F-63000 Clermont-Ferrand, - Centre Jean Perrin, F-63011, Clermont-Ferrand, France. elisabeth.noirault@inserm.fr
Reux
Bastien
B
Debiton
Eric
E
Madelmont
Jean-Claude
JC
Chezal
Jean-Michel
JM
Coudert
Pascal
P
Weber
Valérie
V
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002699:Chlorambucil / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology*; D019788:Fluorodeoxyglucose F18 / Q000494:pharmacology*; D006801:Humans; D020714:Maximum Tolerated Dose; D051379:Mice; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D019788:Fluorodeoxyglucose F18; D002699:Chlorambucil