The alkylating antitumor drug tallimustine does not induce DNA repair.
Tallimustine, an alkylating benzoyl mustard derivative of distamycin A (FCE 24517), is a novel anti-tumor agent. Both its cytotoxic activity against human LoVo cells and nicking efficiency on isolated plasmid DNA were studied in relation to hyperthermic treatment and compared to the effect of doxorubicin, a known non-alkylating anti-tumor agent. The results of this analysis indicate that the cytotoxic activity of tallimustine reflects its direct interaction with the DNA target. The ability of tallimustine to induce DNA repair in human primary normal fibroblasts was monitored by determining both the stimulation of unscheduled DNA synthesis (UDS) and the ability to reactivate a plasmid containing a reporter gene, treated in vitro with tallimustine, in comparison with the effect of UV-C irradiation. The results suggest that human cells able to repair UV-damage arc unable to overcome DNA damage induced by tallimustine. Therefore, the hypothesis that the biological activity of tallimustine is related to its alkylating properties is further supported by the temperature studies and strengthened by the observed inability of cells to repair tallimustine-induced DNA damage.
Rossi
R
R
Istituto di Genetica Biochimica ed Evoluzionistica, C.N.R., Pavia, Italy.
Montecucco
A
A
Capolongo
L
L
Mezzina
M
M
Chevallier-Lagente
O
O
Sarasin
A
A
Ciarrocchi
G
G
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000528:radiation effects; D004278:DNA, Superhelical / Q000187:drug effects* / Q000528:radiation effects; D004214:Distamycins / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D006979:Hyperthermia, Induced; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D004273:DNA, Neoplasm; D004278:DNA, Superhelical; D004214:Distamycins; D009588:Nitrogen Mustard Compounds; C066900:tallimustine; D004317:Doxorubicin; D008156:Luciferases