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

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 (IC 50 ) or lethal concentration 100 (CL 100 )) 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 (RC 0 ), which will define the concentration and time necessary to kill 100 % of the cells and prevent regrowth when drug is removed. The RC 0 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.

Pankiller effect of prolonged exposure to menadione on glioma cells: potentiation by vitamin C

“…The anti-proliferative effect of menadione has been studied in several glioma cell lines and showed IC 50 values ranging between 13.5 μM to ~25 μM [1, 24] . We recently suggested that drug concentrations much higher than the IC 50 might be required to eliminate 100% of tumor cells and that the IC 50 is not the best parameter to evaluate anti-cancer drugs because it does not select for useful clinical drugs [14].

Fig.

…”

“…Cells were routinely cultured as previously described [14]. Patients-derived glioblastoma cells hGCL1- hGCL8 were kindly provided by Dr Peter Siesjö (Lund University).…”

“…In most studies, the fate of surviving cells after short term incubation with drugs is not evaluated. For instance, glioma cells can survive prolonged exposure of anti-neoplastic drugs at concentrations much higher than the IC 50 [14]. At the clinical level, these surviving cells explain the relapse of tumor when the treatment is discontinued and suggest that drugs that kill 100% of tumoral cells (“pankillers”) will be more effective anti-cancer drugs and may, cure cancer.…”

Role of Tumor Suppressor Protein p53 in Apoptosis and Cancer Therapy

“…also granulocyte-Macrophage Colony-Stimulating Factor, Interferon Alpha and Interleukin-2 as Adjuvant Treatment for High-Risk Renal Cell Carcinoma [47] similarlyPre-clinical Validation of Targeted Radionuclide Therapy Using a [ 131 I] Labelled Iodoquinoxaline Derivative for an Effective Melanoma Treatment [48]. Baculovirus expressed tumstatin was used to evaluate its anti-angiogenic and anti-tumarogenic functions such as inhibition of endothelial cell proliferation, cell viability, migration, tube formation, cap dependent protein translation and the associated signaling mechanism including in-vivo tumor study [49]. Regrowth Concentration Zero (RC0) as complementary endpoint parameter evaluates compound candidates during preclinical drug development for cancer treatment [50].…”