Chemosensitivity of Various Peritoneal Cancer Cell Lines to HIPEC and PIPAC: Comparison of an Experimental Duplex Drug to Standard Drug Regimens in Vitro

Invest New Drugs. 2019 Jun;37(3):415-423. doi: 10.1007/s10637-018-0641-6. Epub 2018 Jul 18.

Abstract

We performed an in-vitro study testing the chemosensitivity of peritoneal cancer cell lines (SW620, HCT116, MKN45, 23,132/87, OAW42) to various cytostatic drug regimens. A duplex drug, characterized by reversible linking of the antimetabolites 2'-deoxy-5-fluorouridine (5-FdU) and 3'-C-ethynylcytidine (ECyd), was compared to oxaliplatin or to cisplatin plus doxorubicin. The experiments were designed to reflect the conditions of intraperitoneal chemotherapy. CASY® (Cell Analysis System) technology was used to compare the impact of incubation temperature/duration and drug concentration on the viability of the cancer cell lines versus normal human dermal fibroblasts. Two incubation scenarios were explored: (i) hyperthermic intraperitoneal chemotherapy (HIPEC) with 1 h of incubation at 42 °C, and (ii) pressurized intraperitoneal aerosol chemotherapy (PIPAC) with several successive incubations at 37 °C. Under HIPEC conditions, oxaliplatin induced a potent temperature-dependent growth inhibition of colon cancer cells not seen with the duplex drug. Under PIPAC conditions, the duplex drug achieved the same growth inhibition at a fraction of the dose level required with oxaliplatin. Gastric and ovarian cancer cells were more sensitive to cisplatin plus doxorubicin than to the duplex drug under PIPAC conditions. The duplex drug suggests itself, notably in cases of platinum resistance, as an alternative or addition to intraperitoneal chemotherapies when platinum-based PIPAC technology is used. Using it with HIPEC technology is not recommended. Higher doses of the duplex drug will enhance growth inhibition, albeit at the cost of a severely reduced difference in chemosensitivity between tumor and normal cells. Our findings provide orientation for PIPAC-based personalized intraperitoneal chemotherapy.

Keywords: Chemosensitivity; HIPEC; PIPAC; Peritoneal cancer cell lines; Platinum versus duplex drug.

Publication types

  • Comparative Study

MeSH terms

  • Adult
  • Aged
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects*
  • Cisplatin / pharmacology
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / pathology
  • Cytidine / analogs & derivatives*
  • Cytidine / pharmacology
  • Cytostatic Agents / pharmacology*
  • Deoxyuridine / analogs & derivatives*
  • Deoxyuridine / pharmacology
  • Doxorubicin / pharmacology
  • Female
  • Humans
  • Hyperthermia, Induced*
  • In Vitro Techniques
  • Middle Aged
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / pathology
  • Oxaliplatin / pharmacology
  • Peritoneal Neoplasms / drug therapy*
  • Peritoneal Neoplasms / pathology
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / pathology
  • Tumor Cells, Cultured

Substances

  • 1-(3-C-ethynylribopentofuranosyl)cytosine
  • Cytostatic Agents
  • Oxaliplatin
  • 5-formyl-2'-deoxyuridine
  • Cytidine
  • Doxorubicin
  • Cisplatin
  • Deoxyuridine