Fesoterodine quantification of individual receptor species by selective

InsR uninhibited could overcome any positive effects of IGFR inhibition. Indeed, a recent study by Buck et al . has revealed that anti-IGFR antibody treatment resulted in a compensatory increase in phos- phorylation of InsR, which was associated with fesoterodine resistance to inhibition of IRS and AKT. While OSI-906 treatment resulted in an enhanced reduction of downstream signaling pathways 9 . Second, host toxicity, particularly hyper- glycemia, due to the metabolic effects of the monoclonal antibody could affect response to cytotoxic chemotherapy. Given the long half-life of antibodies, it would be difficult to reduce this toxic effect with this class of drugs.

Finally, as we have outlined, sequencing of the cytotoxic insult with anti-IGFR inhibition may be important. Our data suggest that the cytotoxic agent should precede IGFR/InsR inhi- bition. Again, the long half-life of monoclonal antibodies makes it difficult to achieve this sequencing. In this respect, the TKIs could be more effective in combination with Gemcitabine chemotherapy because of their pharmacokinetic properties. Further clinical development of these agents should focus on appropriate sequencing and scheduling to determine the benefit of these drug combinations. Acknowledgments We thank Dr. Do-Hyung Kim for constructive technical advice on autophagy experiments. We thank Dr. Elizabeth Buck from OSI Pharmaceuticals for providing OSI-906 and valuable 8 Breast Cancer Res Treat discussions in the writing of the manuscript. This work was supported by National Institutes of Health R0CA7485 to DY and National Cancer Institute Cancer Center Support Grant P30077598. 6.

Sachdev D, Hartell JS, Lee AV, Zhang X, Yee D (004) A dominant negative type I insulin-like growth factor receptor inhibits metastasis of human cancer cells. J Biol Chem Pimobendan 74150-27-9 79(6):507–504 Conflict of interest References None. 7. Verbeke G, Molenberghs G (000) Linear mixed models for longitudinal data. In 8. Cullen KJ, Yee D, Sly WS, Perdue J, Hampton B, Lippman ME, Rosen N (990) Insulin-like growth factor receptor expression and function in human breast cancer. Cancer Res 50():48–53 9. Chambers AF (009) MDA-MB-435 and M4 cell lines: identical but not M4 melanoma? Cancer Res 69(3):59–593 . Pegram MD, Pietras R, Bajamonde A, Klein P, Fyfe G (005) Targeted therapy: wave of the future. J Clin Oncol 3(8):776–78 .

Alvarez RH, Valero V, Hortobagyi GN (00) Emerging targeted therapies for breast cancer. J Clin Oncol 8(0):3366–3379 3. Pollak M (008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8():95–98 4. Sachdev D (008) Regulation of breast cancer metastasis by IGF signaling. J Mammary Gland Biol Neoplasia 3(4):43–44 5.  buy Pimobendan Sepp-Lorenzino L (998) Structure and function of the insulin- like growth factor I receptor. Breast Cancer Res Treat 47(3):35–53 6. Bailyes EM, Nave BT, Soos MA, Orr SR, Hayward AC, Siddle K (997) Insulin receptor/IGF-I receptor hybrids are widely dis- tributed in mammalian tissues: quantification of individual receptor species by selective immunoprecipitation and immuno- blotting. Biochem J 37():09–5 7. Sachdev D, Yee D (00) The IGF system and breast cancer. Endocr Relat Cancer 8(3):97–09 8. Weroha SJ, Haluska P (008) IGF- receptor inhibitors in clinical trials—early lessons. J Mammary Gland Biol Neoplasia 3(4): 47–483 9. Hewish M, Chau I, Cunningham D (009) Insulin-like growth  preparation factor receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine. Recent Pat Anticancer Drug Discov 4():54–7 0. Ji QS, Mulvihill MJ, Rosenfeld-Franklin M, Cooke A, Feng L, Mak G, O’Connor M, Yao Y, Pirritt C, Buck E et al (007) A novel, potent, and selective insulin-like growth factor-I receptor kinase inhibitor blocks insulin-like growth factor-I receptor sig- naling in vitro and inhibits insulin-like growth factor-I receptor dependent tumor growth in vivo. Mol Cancer Ther 6(8): 58–67 . Mulvihill MJ, Cooke A, Rosenfeld-Franklin M, Buck E, Foreman K, Landfair D, O’Connor M

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