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Part-IIIAdvances Dihydropyridines and …B859-35, a DHP, which was previously shown in vitro to be highly effective in reversingMDR of Pgp positive tumor cell lines, such as the adriamycin (ADR) resistanterythroleukemia F4-6RADR cells. In in vivo studies, B859-35 was highly active inreducing the number of viable cells in the resistant tumor nodule by 67±9%. This modelprovides evidence that even in vivo, MDR modulators can be effective in reversing drugresistance. In addition, it presents a potentially useful and rapid preclinical system for invivo studies on the modification of drug resistance. 100The modulatory activity of the novel pyridine analogue PAK-104P on MRP-mediatedresistance to doxorubicin and paclitaxel was investigated in two doxorubicin-selectedhuman tumor cells [HT1080/DR4 (sarcoma) and HL60/ADR (leukemia)]. Theexperiment demonstrated that PAK-104P was effective in restoring cellular doxorubicinconcentrations in resistant cells to levels comparable to those obtained in parental cells. Inaddition to reversing Pgp-mediated MDR, the pyridine analogue provides an example ofan effective in vivo modulator of MRP-mediated MDR. 101From QSAR studies of several hundreds of DHPs, seven DHPs were found to be veryactive. From these predictions, manidipine (CV-4093) 56, a newly synthesized DHPscalcium channel blocker, were predicted to be an extremely active MDRR agent. Theprobability for the DHP to show MDRR activity is very high (99%), owing to thepresence of several biophores. 102411