Regrowth Concentration Zero (RC0) as Complementary Endpoint Parameter to Evaluate Compound Candidates During Preclinical Drug Development for Cancer Treatment

Avramidis Dimitrios

doi:10.4172/1948-5956.1000003

Abstract

The screening process for potential anticancer drugs involves expensive and time consuming preclinical and clinical trials (CT) before a drug is approved for clinical use (CU). At present, there is a “bottleneck” at the CT/CU transition because many drugs that showed promising results during preclinical research did not pass clinical trials. We speculated that the endpoint parameters (the inhibitory concentration 50 (IC50) or lethal concentration 100 (CL100)) commonly used in proliferation assays for short-term periods (24-72 h) are not useful to predict the antiproliferative effect in vivo, especially during clinical trials. We propose the use of a parameter, regrowth concentration 0 (RC0), which will define the concentration and time necessary to kill 100 % of the cells and prevent regrowth when drug is removed. The RC0 might introduce a new bottleneck at the preclinical stage, “preclinical bottleneck”, that will select for drugs with more chances to pass clinical trials and improve the success rate of anticancer screening programs. Our proposal is supported by experiments done with the DBTRG-05MG human glioma cell lines exposed to short and long-term incubation with three different DNA replication inhibitors (aphidicolin, hydroxyurea and etoposide) and retrospective analysis of clinical trials for these drugs.

Highlights

The standard approach to evaluate novel compounds for cancer treatment after drug synthesis or discovery is based in preclinical testing and clinical trials (Figure 1 top)
In this paper we propose that the success rate and cost benefit for drug development could be improved by introducing a “bottleneck” during the preclinical stage (“preclinical bottlennraaemcleke”toe)fruoisnuinrstgepartohdpeoofssoIaClc5ai0slloesrduLpRpCCo10r00te((sdFeiebgyugrlaoess1searBriyeo)sttaoosmf e)en.xdTppehoreiinmrtaetpnioats-using prolonged exposure to three classical DNA replication inhibitors with different mechanism of action in the human DBTRG-05MG glioma cell line and a retrospective analysis of clinical trials with these same drugs
We used the human glioma cell line DBTRG-05MG as an experimental system to retrospectively analyze the failure of several drugs that inhibit in vitro cell proliferation of cancer cell lines during clinical trials

Summary

Introduction

The standard approach to evaluate novel compounds for cancer treatment after drug synthesis or discovery is based in preclinical testing and clinical trials (Figure 1 top). In case the compound shows promising in vivo effect on tumor growth, acceptable side effects and toxicity, the drug is considered a good candidate to be tested in clinical trials. These stages are associated with a significant percentage of the total cost of the entire drug evaluation process (DiMasi et al, 2003; Emanuel et al, 2003). The outcome has been disappointing and sometimes

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