title: Evaluation of melphalan, oxaliplatin, and paclitaxel in colon, liver, and gastric cancer cell lines in a short-term exposure model of chemosaturation therapy by percutaneous hepatic perfusion.
abstract: BACKGROUND
  The goal of this study was to determine whether liver, gastric, or colonic cancer may be suitable targets for chemosaturation therapy with percutaneous hepatic perfusion (CS-PHP) and to assess the feasibility of utilizing other cytotoxic agents besides melphalan in the CS-PHP system.
  
  
  METHODS
  Forty human cell lines were screened against three cytotoxic chemotherapeutic agents. Specifically, the dose-dependent effect of melphalan, oxaliplatin, and paclitaxel on proliferation and apoptosis in each cell line was evaluated. These agents were also evaluated for their ability to induce apoptosis in normal primary human hepatocytes. A high-dose short-term drug exposure protocol was employed to simulate conditions encountered during CS-PHP.
  
  
  RESULTS
  The average concentration of melphalan required for inducing significant apoptosis was 61 μM, or about 3-fold less than the theoretical concentration of 192 μM, achieved in the hepatic artery during CS-PHP dosing with melphalan. Additionally, we found that gastric cancer cell lines were 2-5 fold more sensitive to apoptosis than liver cancer cell lines to all three compounds, suggesting that in addition to colonic and gastric cancer metastases to the liver, primary gastric cancer may also be amenable to management by CS-PHP using an appropriate therapeutic agent. Significantly, at concentrations that are predicted using the CS-PHP system, these agents caused apoptosis of colonic, gastric, and liver cancer cells but were not toxic to primary human hepatocytes.
  
  
  CONCLUSIONS
  The compounds tested are potential candidates for use in the CS-PHP system to treat patients with gastric and colonic metastases, and primary cancer of the liver.
authors: Director of Pharmaceutical Research, Delcath Systems, Inc., 566 Queensbury Avenue, Queensbury, NY 12804, USA. ruzgare@delcath.com
authors: Rajneesh P
authors: RP
authors: Uzgare
authors: Timothy P
authors: TP
authors: Sheets
authors: Daniel S
authors: DS
authors: Johnston
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005434:Flow Cytometry; D006499:Hepatic Artery / Q000166:cytology / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008558:Melphalan / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D017239:Paclitaxel / Q000494:pharmacology*; D010477:Perfusion; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D017239:Paclitaxel; D008558:Melphalan
keywords: Chemosaturation therapy; melphalan; percutaneous hepatic perfusion; platinum agents; taxanes