Differential effects of Toremifene on Doxorubicin, Vinblastine and Tc-99m-sestamibi in P-glycoprotein-expressing Breast and Head and Neck Cancer cell lines
Document Type
Article
Department
Pathology and Microbiology
Abstract
The effect of toremifene on P-glycoprotein-mediated multidrug resistance (MDR) in breast and head and neck cancer cell lines was measured in vitro and in vivo. Pgp expression was low and high, respectively, in drug-sensitive (MCF7-S, KB) and drug-resistant (MCF7-R, MCF7-R1, KBV1) cell lines. Toremifene (7.5 μM) significantly enhanced cytoplasmic and nuclear accumulation of doxorubicin in drug-resistant cells. Toremifene (10 μM) increased the in vitro cytotoxicity of doxorubicin in drug-resistant breast cancer cells (13-fold and 21-fold for MCF7-R and MCF7-R1, respectively) without affecting the sensitivity of MCF7-S cells. Similarly, toremifene (10 μM) caused a 12-fold increase in the sensitivity of KBV1 cells to vinblastine. In contrast, toremifene (5 μM) reduced the net uptake of the radiolabelled Pgp substrate, Tc-99m-sestamibi, in the Pgp-overexpressing cell lines by factors of 0.32 and 0.42 for MCF7-R1 and KBV1 cells, respectively (p<0.01), and, to a lesser extent, by corresponding factors of 0.89 and 0.86 in the drug-sensitive cell lines (p<0.05 and p>0.05, respectively). In nude mice bearing both KB and KBV1 xenograft tumours, significantly higher tumour levels of Tc-99m-sestamibi were recorded in KB tumours compared with KBV1 tumours. After 3 days of treatment with intraperitoneal toremifene (25 mg/kg), tumour levels of Tc-99m-sestamibi were reduced in KB and KBV1 tumours but only statistically significantly for KB tumours. Toremifene is a potent MDR modulating agent with respect to chemotherapeutic agents but has the opposite effect with respect to Tc-99m-sestamibi. This finding is of importance in view of the widespread use of Tc-99m-sestamibi as an imaging surrogate for a chemotherapeutic agent.
Publication (Name of Journal)
Acta Oncologica
Recommended Citation
Mubashar, M.,
Harrington, K. J.,
Chaudhary, K. S.,
Lalani, E.,
Stamp, G. W.,
Peters, A. M.
(2004). Differential effects of Toremifene on Doxorubicin, Vinblastine and Tc-99m-sestamibi in P-glycoprotein-expressing Breast and Head and Neck Cancer cell lines. Acta Oncologica, 43(5), 443-452.
Available at:
https://ecommons.aku.edu/pakistan_fhs_mc_pathol_microbiol/342