Contributing factors of temozolomide resistance in MCF-7 tumor xenograft models

Vasculature mediated drug resistance in tumors was studied in female SCID mice bearing wild type MCF-7 and adriamycin resistant MCF-7/ADR xenograft using temozolomide (TMZ). A strong tumor growth inhibitory effect of TMZ treatment was observed in MCF-7 tumors during the initial treatment phase with subsequent relapse, but not in MCF-7/ADR tumors. Non-invasive MRI measurements of tumor vascular volume and vascular permeability-surface area product (PS) demonstrated significant reduction of PS in long-term treated MCF-7, but not in MCF-7/ADR tumors. O⁶-Methylguanine-DNA methyltransferase (MGMT) mRNA, and VEGF expression was analyzed using real-time RT-PCR and ELISA, respectively. No significant changes in MGMT mRNA and VEGF expression were observed in either MCF-7 or MCF-7/ADR tumors. However, in vitro incubation of MCF-7 cells with TMZ did induce the expression of MGMT mRNA. In addition, p53 and p21 levels were scored by immunoblotting. Exposure of cells to TMZ did not affect either the p21 or the p53 expression in both MCF-7 and MCF-7/ADR cells. The absence of these molecular responses to TMZ treatment in MCF-7 tumors in vivo supports the possibility that the onset of cancer drug resistance is associated with reduced PS, which can decrease delivery of the drug to cancer cells.