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.