Thus, it is plausible that a chronic exposure of osteosarcoma cells to DOX does not always affect other mechanisms of resistance to MTX, such as modulation of the expression of MTX target dihydrofolate reductase (DHFR), or to CIS, such as the deregulation of BER-/NER-mediated DNA repair or the inactivation trough detoxification enzymes, like GSTP1-1 [19,45,46]. This evidence concerns the gene DHFR and in situ carcinoma.