ABSTRACT
Drug optimization, which improves drug potency/specificity by structure‒activity relationship (SAR) and drug-like properties, is rigorously performed to select drug candidates for clinical trials. However, the current drug optimization may overlook the structure‒tissue exposure/selectivity-relationship (STR) in disease-targeted tissues vs. normal tissues, which may mislead the drug candidate selection and impact the balance of clinical efficacy/toxicity. In this study, we investigated the STR in correlation with observed clinical efficacy/toxicity using seven selective estrogen receptor modulators (SERMs) that have similar structures, same molecular target, and similar/different pharmacokinetics. The results showed that drug's plasma exposure was not correlated with drug's exposures in the target tissues (tumor, fat pad, bone, uterus), while tissue exposure/selectivity of SERMs was correlated with clinical efficacy/safety. Slight structure modifications of four SERMs did not change drug's plasma exposure but altered drug's tissue exposure/selectivity. Seven SERMs with high protein binding showed higher accumulation in tumors compared to surrounding normal tissues, which is likely due to tumor EPR effect of protein-bound drugs. These suggest that STR alters drug's tissue exposure/selectivity in disease-targeted tissues vs. normal tissues impacting clinical efficacy/toxicity. Drug optimization needs to balance the SAR and STR in selecting drug candidate for clinical trial to improve success of clinical drug development.
ABSTRACT
Purpose To investigate the role of urokinase plasminogen activator (uPA),uPA receptor (uPAR),tissue type plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1) in the invasiveness of human breast cancer cells. Methods Three human breast cancer cell lines with different invasive ability were taken as research targets.RT-PCR and milk plates methods were used to detect the expression of uPA system members and the PA activities,respectively.Modified Boyden's chamber model was employed to detect the invasive ability of cancer cell. Results MDA-MB-231 could express high level of uPA,uPAR,PAI-1 and low level of tPA.MDA-MB-435 could express lower level of uPA and hight level of tPA,but no PAI-1 and uPAR were detected.MCF-7 could express lower level of uPAR and high level of PAI-1,but no uPA and tPA were detected.MDA-MB-231 cells showed the highest total PA and uPA activity.MDA-MB-435 cells also showed high total PA activity,but almost all the activity owed to tPA.MCF-7 showed almost no PA activity.Correlated with their PA activities,MDA-MB-231 was found the most invasive in vitro,followed by MDA-MB-435,and MCF-7 almost had no invasive ability.The antibodies against uPA and uPAR were significantly effective in reducing the matrigel invasiveness of MDA-MB-231 by approximately 83.1% and 43.9% respectively (P<0.05). Conclusions Co-expression of uPA,uPAR and PAI-1 in human breast cancer highly correlates with the invasiveness in vitro.