The inverse relationship between reduced folate carrier function and pemetrexed activity in a human colon cancer cell line

Molecular Cancer Therapeutics
Shrikanta ChattopadhyayI David Goldman

Abstract

Pemetrexed, a new generation antifolate recently approved for the treatment of mesothelioma and non-small cell lung cancer, is an excellent substrate for the reduced folate carrier (RFC). To explore the carrier's effect on pemetrexed activity, RFC was inactivated in HCT-15 colon cancer cells by mutagenesis and PT632 selective pressure. A clone (PT1) was obtained with a glycine to arginine substitution at amino acid 401, resulting in the loss of RFC function. PT1 cells were resistant to PT632 (178-fold), methotrexate (4-fold), and ZD1694 (Tomudex, raltitrexed; 20-fold), but were 3-fold collaterally sensitive to pemetrexed when grown in 25 nmol/L of 5-formyltetrahydrofolate. PT1 cells transfected with wild-type RFC had antifolate sensitivities comparable to that of wild-type HCT-15 cells, indicating that the RFC mutation was the sole basis for resistance. Folate pools were contracted in PT1 cells by 32% or 60%, as measured by radiolabeling intracellular folates or by an enzyme binding assay, respectively. This was reflected in marked (6.5-fold) collateral sensitivity to trimetrexate. The initial uptake of pemetrexed in PT1 cells was markedly reduced ( approximately 85%) but intracellular pemetrexed levels increased to approximate...Continue Reading

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Citations

May 17, 2011·Annual Review of Nutrition·Rongbao ZhaoI David Goldman
Mar 16, 2007·Expert Opinion on Emerging Drugs·Yesid AlvaradoFrancis J Giles
Sep 13, 2011·Expert Opinion on Investigational Drugs·Elena GalvaniElisa Giovannetti
Mar 20, 2013·Molecular Aspects of Medicine·Rongbao Zhao, I David Goldman
Aug 28, 2012·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Nitzan Gonen, Yehuda G Assaraf
Apr 24, 2012·Hematology/oncology Clinics of North America·Michele VisentinI David Goldman
Jul 12, 2011·Revue des maladies respiratoires·I Rouquette, J Mazieres
Jul 24, 2010·The Journal of Thoracic and Cardiovascular Surgery·Aneil A MujoomdarDavid J Sugarbaker
Dec 23, 2015·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Laura TaddiaMaria Paola Costi
Jan 27, 2009·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Ignace VergoteJalid Sehouli
Apr 8, 2015·Cancer Chemotherapy and Pharmacology·Rongbao ZhaoI David Goldman
Sep 26, 2017·Annals of Oncology : Official Journal of the European Society for Medical Oncology·E GiovannettiG J Peters
Oct 17, 2006·Molecular Cancer Therapeutics·Shrikanta ChattopadhyayI David Goldman
Feb 20, 2007·Molecular Cancer Therapeutics·Shrikanta ChattopadhyayI David Goldman
Nov 1, 2017·Annals of Oncology : Official Journal of the European Society for Medical Oncology·E GiovannettiG J Peters

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