In vitro pharmalogic rationale for intraperitoneal regional chemotherapy

We performed basic in vitro studies on cell lines and individual tumor cell suspensions to support the concept of intraperitoneal regional chemotherapy, and to improve the rationale for drug selection in this regional chemotherapeutic method. We defined the concentration-response behavior and the dependence of drug cytotoxicity on time using the two human colorectal carcinoma cell lines HT29 and NMG 64/84. In addition, the drugs concentration-response behavior and cytotoxic potency for IPRC after a single drug exposure at 10 micrograms/ml (5-FU at 100 micrograms/ml) was preclinically defined with in vitro phase II studies using single cell suspensions of human solid tumor biopsies in the human tumor colony assay (HTCA). The drugs doxorubicin (ADM), cisplatin (CDDP), epidoxorubicin (EPI), 5-fluorouracy (5-FU), 5-fluorodeoxyuridine (5-FUDR), melphalan (LPAM), mitomycin C (MMC), and mitroxantrone were incubated at increasing concentrations up to 1000 micrograms/ml at 10, 30, 60, 360, and 1440 minutes with the cell lines. These drugs, as well as vindesine (VDS) and mafosfamide (MAF) were also tested in the HTCA at increasing concentrations. The HTCA response rates at 10 micrograms/ml (5-FU and MAF at 100 micrograms/ml) were used for in vitro phase II comparisons of potential drug clinical activities. All test drugs showed a time- and concentration-dependent cytotoxic activity against the cell lines. Based on the cytotoxicity test results with HT29 and NMG 64/84, specific times were recommended for clinical therapy with each drug. In the HTCA, the drugs showed different cytotoxic concentration responses. The concentration-response behavior of each drug varied in individual tumor biopsies of the same histology. Comparing the response rates at 1 microgram/ml (5-FU and MAF 10 micrograms/ml) and 10 micrograms/ml (5-FU and MAF 100 micrograms/ml), an overall increase of in vitro response by a factor of 2.1 +/- 0.7 (1.1-3.7) was noted. We were able to prove this principle qualification of various test drugs in our in vitro studies and to suggest the optimal exposure times for their use in intraperitoneal chemotherapy. Based on these results, NOV was successfully used in an IPRC clinical study.