In vitro-in vivo Correlation in Anticancer Drug Sensitivity Test Using AUC-Based Concentrations and Collagen Gel Droplet-Embedded Culture

Abstract

To improve the ability of an in vitro drug sensitivity test to predict in vivo effects, we applied a drug concentration that was pharmacokinetically equivalent to plasma levels and collagen gel droplet-embedded culture with a high cloning efficiency. We reported that the cell-killing effect of cell cycle phase-nonspecific drugs such as mitomycin C, cisplatin and Adriamycin depends on the area under the drug concentration-time curve (AUC). The plasma AUC values of these drugs were estimated after an injection into nude mice at the maximal tolerated doses (MTD). Tumor cells isolated from human tumor xenografts implanted into nude mice and cultured in collagen gel droplets were exposed to drugs under conditions that can reproduce the plasma AUC in vitro. The in vitro sensitivity to a drug was compared with the in vivo response of the same tumor treated with the MTD of the drug. When the criterion of sensitivity was taken as 50% or less of the growth inhibition (growth rate of treated group/that of control group, T/C), the correlation between the in vitro and in vivo growth inhibition of all 3 drugs tested was relatively high (86% of the true-positive rate, 82% of the true-negative rate and 83% of the correlation rate).

Clinical study on collagen gel droplet-embedded culture drug sensitivity test for multidrug combination chemotherapy and super selective intra-arterial infusion chemoradiotherapy in oral squamous cell carcinoma

“…On the other hand, the CD-DST that we performed in this study had a potential for a high success rate on initial culture, needed a small number of cells, and used serum-free culture medium and image colorimetry to eliminate the influence of fibroblasts. The CD-DST has the advantage of using an anticancer drug contact concentration that is comparable to the clinical therapeutic dose (5,6,10,25). In fact, the primary measurement success rate of the CD-DST was reported to be 87.5% in colorectal cancer, 79.2% in lung cancer, and 84.3% in breast cancer (11,26,27).…”

Chemosensitivity of Uterine Cervical Cancer Demonstrated by the Histoculture Drug Response Assay

“…Currently, several chemosensitivity tests are clinically applicable; for examples, the MTT assay (Cole 1986), the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay (O'Toole et al 2003), the HDRA (Hoffman 1991b(Hoffman , 1993aRobbins et al 1994;Furukawa et al 1995;Brown and Markman 1996), and collagen gel droplet-embedded culture drug sensitivity test (CD-DST) (Inaba et al 1996;Takamura et al 2002). The monolayer culture MTT assay is based on the reduction of MTT by mitochondrial succinic dehydrogenase which is in living cells.…”

Prediction of 5-Fluorouracil and Cisplatin Synergism for Advanced Gastrointestinal Cancers Using a Collagen Gel Droplet Embedded Culture

“…22 The sensitivity and specificity of the assay have been reported to be 83%-100% and 75%-86%, respectively. 22,29 In this study seven cases dropped out because of an insufficient number of cancer cells due to contamination of a large number of fibroblasts. As a result, further evaluations are needed for cases in which a large fraction of the tumor is composed of fibroblasts.…”