Increased growth inhibition and DNA lesions in human colon adenocarcinoma cells treated with methotrexate or 5-fluorodeoxyuridine followed by calmodulin inhibitors.

The antineoplastic agents methotrexate and 5-fluorodeoxyuridine induce DNA lesions, although the drugs are not incorporated into DNA. The lesions arise as a result of reduced repair of damage occurring in DNA independently of the treatment with antineoplastic agents. When cells containing DNA lesions are treated with calmodulin inhibitors (W-7, phenothiazine, promethazine), the amount of lesions is increased, in all probability due to reduced DNA repair. This is paralleled by increased growth inhibition. Hence by inhibiting calmodulin, one can modulate the levels of DNA lesions and change the growth-inhibitory effect induced by methotrexate or 5-fluorodeoxyuridine. This strongly supports the importance of this type of DNA lesion in the toxic effects induced by the drugs.