Change in plasma lactate concentration during arctigenin administration in a phase I clinical trial in patients with gemcitabine-refractory pancreatic cancer

PLoS One. 2018 Jun 1;13(6):e0198219. doi: 10.1371/journal.pone.0198219. eCollection 2018.

Abstract

Arctigenin is evaluated for antitumor efficacy in patients with pancreatic cancer. It has an inhibitory activity on mitochondrial complex I.Therefore, plasma lactate level of patients after arctigenin administration was evaluated for biomarker of clinical response and/or adverse effect. Plasma lactate level in 15 patients enrolled in a Phase I clinical trial of GBS-01 rich in arctigenin was analyzed by colorimetric assay. Statistical analyses for association of plasma lactate and clinical responses, pharmacokinetics of arctigenin, and background factors of each patient by multivariate and univariate analyses.In about half of the patients, transient increase of lactate was observed. Correlation between plasma lactate level and pharmacokinetic parameters of arctigenin and its glucuronide conjugate, and clinical outcome was not detected. Regarding to the determinant of lactate level, only slight association with liver function test was detected. Plasma lactate level is primary determined by reutilization rather than production for antitumor effect and dose not serve as a biomarker. Arctigenin, inhibition of mitochondrial complex I, plasma lactate concentration, phase I clinical trial of GBS-01, Cori cycle.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Arctium* / chemistry
  • Area Under Curve
  • Biomarkers / blood
  • Carcinoma, Adenosquamous / blood*
  • Carcinoma, Adenosquamous / drug therapy
  • Carcinoma, Pancreatic Ductal / blood*
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Cell Line, Tumor
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Drugs, Chinese Herbal / pharmacokinetics
  • Drugs, Chinese Herbal / therapeutic use*
  • Furans / pharmacokinetics
  • Furans / therapeutic use*
  • Gemcitabine
  • Gluconeogenesis / drug effects
  • Humans
  • Kaplan-Meier Estimate
  • Kidney / physiopathology
  • Lactic Acid / blood*
  • Lignans / pharmacokinetics
  • Lignans / therapeutic use*
  • Liver / physiopathology
  • Mitochondria / drug effects
  • Oxidative Phosphorylation / drug effects
  • Pancreatic Neoplasms / blood*
  • Pancreatic Neoplasms / drug therapy
  • Plant Extracts / therapeutic use*

Substances

  • Antineoplastic Agents, Phytogenic
  • Biomarkers
  • Drugs, Chinese Herbal
  • Furans
  • Lignans
  • Plant Extracts
  • Deoxycytidine
  • Lactic Acid
  • arctigenin
  • Gemcitabine

Associated data

  • UMIN-CTR/UMIN000005785

Grants and funding

This work was supported in part by grants for Clinical Trial on Development of New Drugs and Medical Devices from the Ministry of Health, Labor and Welfare and Project for Development of Innovative Research on Cancer Therapeutics from Ministry of Education, Culture, Sports, Science and Technology. S. Kishino have received the commissioned research funding from Kracie Pharmaceutical Company within one year. S.Y. is an employee of Kracie Pharmaceutical Company. Kracie pharmaceutical company developed GBS-01 under the collaboration with M. I. and H. E. and made GBS-01 available for a phase I clinical trial (UMIN000005785) as described in Materials and methods of the manuscript. The funder provided support in the form of salaries for S.Y., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.