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Contributing factors of temozolomide resistance in MCF-7 tumor xenograft models
Yoshinori Kato1, Baasil Okollie, Venu Raman
1Department of Radiology, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ykato@mri.jhu.edu
Abstract:
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. O(6)-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.
Insights
Temozolomide (TMZ) shows initial tumor inhibition but resistance develops. Reduced vascular permeability (PS) in tumors may cause drug resistance by limiting drug delivery.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Drug resistance is a major challenge in cancer therapy.
- Tumor vasculature plays a critical role in drug delivery and efficacy.
- Understanding resistance mechanisms is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of tumor vasculature in mediating resistance to temozolomide (TMZ).
- To compare the effects of TMZ on drug-sensitive (MCF-7) and drug-resistant (MCF-7/ADR) breast cancer xenografts.
- To explore potential molecular markers associated with TMZ resistance.
Main Methods:
- Utilized female SCID mice bearing MCF-7 and MCF-7/ADR xenografts.
- Administered temozolomide (TMZ) and monitored tumor growth.
- Performed non-invasive MRI to measure tumor vascular volume and permeability-surface area product (PS).
- Analyzed O(6)-Methylguanine-DNA methyltransferase (MGMT) and VEGF expression via RT-PCR and ELISA.
- Assessed p53 and p21 protein levels using immunoblotting.
Main Results:
- TMZ exhibited significant tumor growth inhibition in MCF-7 tumors initially, followed by relapse, but not in MCF-7/ADR tumors.
- MRI revealed a significant reduction in PS in long-term TMZ-treated MCF-7 tumors, but not in MCF-7/ADR tumors.
- No significant changes in MGMT or VEGF expression were observed in vivo, though in vitro TMZ induced MGMT mRNA in MCF-7 cells.
- p53 and p21 levels remained unaffected by TMZ treatment in both cell lines.
Conclusions:
- Reduced vascular permeability (PS) in tumors may be a key factor in the development of temozolomide resistance.
- Decreased PS can limit the delivery of TMZ to cancer cells, contributing to treatment failure.
- Further research into vascular-targeted therapies could enhance chemotherapy efficacy.
