| BACKGROUND: Oral bioavailability of many anticancer drugs is poor and highly variable. This is a major impediment to the development of new generation drugs in oncology, particularly those requiring a chronic treatment schedule, a.o. the farnesyltransferase inhibitors. Limited bioavailabi1ity is mainly due to: 1) cytochrome P450 (CYP) activity in gut wall and liver, and 2) drug transporters, such as P-gp and breast cancer resistance protein (BCRP) in gut wall and liver. Shared substrate drugs are affected by the combined activity of these systems. Available preclinical in vitro and in vivo models are in many cases only poorly predictive for oral drug uptake in patients because of a.o. interspecies differences in research CYP drug metabolism and intestinal drug transporting systems. Clearly, novel and in part humanized systems that allow reliable translation of preclinical results to the clinic are strongly needed. Our previous work, also using P-gp knockout (KO) mice, already showed that P-gp has a major effect on the oral bioavailability of several drugs and that blockers of P-gp can drastical1y improve oral bioavailability of paclitaxel and other drugs in mice and humans (Cel1 1994;77:491; PNAS 1997;94:2031; Lancet 1998;352:285). This work revealed, however, that apart from P-gp other drug-transporting systems and CYP effects also determine overall oral drug uptake. Indeed, we recently demonstrated that blockade of BCRP profoundly increased the oral bioavailability of topotecan in mice. OBJECTIVE: The objective of this project is to develop and analyze additional transgenic and KO mouse models and in vitro metabolism systems to complete our insights into the mechanisms governing efficacy of oral drug uptake. These insights from the laboratory will then be extensively explored in patients using various blockers to optimize bioavailability of anticancer drugs. APPROACH: An integrated approach of preclinical and clinical studies wil1 be followed to fulfill our objectives. - Preclinical studies: As CYP3A is the major drug-metabolizing system in humans, we will first generate and analyze constitutive and conditional liver- and intestine-specific Cyp3a KO mice and human CYP3A4 transgenic mice to define the role of intestinal and hepatic Cyp3a in oral drug fate. Next, drug disposition in combined Cyp3a and P-gp, or Cyp3a and Bcrp KO mice (under development) will be investigated. Drug metabolism and the effects of various blockers will be assessed in liver and intestinal microsomes or slice preparations of wild-type, transgenic and KO mice, rats and humans. Based on the insights obtained, we will test (novel) drugs combined with blockers of Cyp3a, P-gp, and/or Bcrp in various mouse models, and test toxicity/antitumor efficacy. Bioanalytical methods for the drugs and metabolites will be developed, mostly based on LC/MS/MS technologies. - Clinical studies: The preclinical results will guide us to design protocols in which we will investigate in patients the oral pharmacology of selected anticancer drugs together with appropriate blockers of CYP, P-gp, and/or BCRP to minimize inter- and intra-patient variability and to improve bioavailability. Oral pharmacokinetics, metabolite profiles and toxicity will be assessed. Antitumor efficacy will be explored in Phase II trials when indicated. In the short term we will initiate a clinical study to improve the oral pharmacokinetics of topotecan and GG211 by co-administration of the BCRP blocker GG918. ELEMENTS OF INNOVATION: The integration of KO and transgenic mouse models for defined drug-handling genes, combined with derived in vitro metabolism models to predict and optimize oral bioavailability of new anticancer drugs is innovative. Rational development of oral treatment schedules for anticancer drugs, using selective inhibition of well-characterized targets (CYP , P-gp, BCRP) is new. RELEVANCE FOR CLINICAL CANCER RESEARCH AND CLINICAL PRACTICE: We expect that the concepts from this 'translational' project will greatly aid to develop and to optimize oral treatment strategies and in particular new generation anticancer drugs, such as farnesyltransferase inhibitors, angiogenesis inhibitors, metalloproteinase inhibitors and chemopreventive agents. |
