Lack of in Vitro – in Vivo Correlation of a Novel Investigational Anticancer Agent, SH 30

Abstract

In solid tumors, the reasons for the lack of in vitro andin vivo correlation of drugactivities are multifold and includespermeability to the tumor cells,interstitial hypertension and metabolicdegradation. So, it is important to studythe permeability and metabolic dispositionof new compounds early in discovery anddevelopment of anticancer drugs. Anexperimental anti-cancer drug, SH 30demonstrated highly selective and potentcytotoxic activity against a number ofmulti-drug resistant tumor cell lines in vitro. However, it was inactive in amurine tumor model. This study wasconducted to identify the barriers thatresult in lack of correlation between in vitro and in vivo cytotoxicactivity of novel anticancer agents. Twoimportant barriers: physical(permeability) and metabolic (enzymaticinactivation) to poor delivery of SH 30 tosolid tumors were investigated in thisstudy. Tumors were sliced to separate thevascular and avascular sections. Theconcentrations of the drug at variousregions of the tumor after single andmultiple doses were investigated todetermine the permeability barrier. Thepermeability barrier was also probed usingtwo in vitro model systems, namely,matrigel® films representing extracellularmatrix and caco-2 multilayer cell culturesthat simulate solid tumors. The drug andits metabolite concentrations weredetermined in the plasma and tumors todetermine the metabolic barrier to the drugcytotoxic action. The metabolic barrierwas further probed using in vitromouse hepatocytes and liver microsomepreparations. Our examination revealed themetabolic barrier to be the majorcontributor to the ineffectiveness of SH 30in vivo. Examination ofconcentration of the drug across variousregions of the tumor corroborated by datafrom in vitro permeation studiessuggested that, for SH 30, permeabilitybarrier did not exist. After singleinjection, the concentrations of SH 30 andits metabolites in plasma and tumor werecomparable to another investigational drugwith similar features (XK 469). Contraryto day 1, after 8 consecutive days ofadministration, SH 30 concentrations weresignificantly lower, while the metabolitesconcentrations were higher, suggestingextensive metabolism due to induction ofenzyme(s). The in vitro hepatocytesand liver microsome results also showed SH30 biotransformation to the samemetabolites. Neither drug penetration, nordrug distribution into regions of thetumors distal to vasculature were impeded. The inactivity of SH 30 in vivo isprimarily due to induction of extensivemetabolism to inactive metabolites. Thismetabolism prevents adequate drug levelsbeing achieved in the tumor.