Induction of plasminogen activator by alkylating agents in a repair defective human glioblastoma cell strain.

Alkylating agents, mechlorethamine and N-methyl-N'-nitro-N-nitrosoguanidine, induce the production of plasminogen activator in U-87MG cells, an alkylation DNA repair deficient (Mer-) human glioblastoma strain. Enzyme induction was not observed, however, in U-178MG and SH-101 cells, alkylation repair proficient (Mer+) glioblastoma strains, or in HeLa cells, which reactivated and supported well the growth of alkylation damaged adenovirus 3. In the alkylation repair defective U-87MG strain, enhanced production of plasminogen activator occurred in a narrow concentration range of treatment with either alkylating agent, causing a 20 to 50% inhibition of [3H]thymidine incorporation. Maximum plasminogen activator induction was observed between 32 and 48 h after alkylation treatment and the levels of enzyme produced were 5 to 10 times those of untreated control levels. This alkylation dependent enzyme induction required protein synthesis for it did not occur in the presence of cycloheximide. It was hence concluded that plasminogen activator induction in alkylation repair deficient human cells is caused by unrepaired DNA damage and that it may represent an eukaryotic SOS-like function. In addition, plasminogen activator induction may be useful as a sensitive assay for the identification of alkylation repair defective human tumors for which the susceptibility to alkylation chemotherapy should be expected to increase.