Collateral sensitivity to gemcitabine (2',2'-difluorodeoxycytidine) and cytosine arabinoside of daunorubicin- and VM-26-resistant variants of human small cell lung cancer cell lines

Biochemical Pharmacology
Andries M BergmanGodefridus J Peters

Abstract

Multidrug resistance (MDR), characterized by a cross-resistance to many natural toxin-related compounds, may be caused either by overexpression of a drug efflux pump such as P-glycoprotein, (P-gP), multidrug resistance proteins MRP1-3, or BCRP/MXR or, in the case of DNA topoisomerase II active drugs, by a decrease in the enzymatic activity of the target molecule termed altered topoisomerase MDR (at-MDR). However, human small cell lung carcinoma (SCLC) cell lines showed a collateral sensitivity to 2',2'-difluorodeoxycytidine (gemcitabine, dFdC) and 1-beta-D-arabinofuranosylcytosine (ara-C). H69/DAU, a daunorubicin (DAU)-resistant variant of H69 with a P-gP overexpression, and NYH/VM, a VM-26 (teniposide)-resistant variant of NYH with an at-MDR, were both 2-fold more sensitive to gemcitabine and 7- and 2-fold more sensitive to ara-C, respectively. MDR variants had a 4.3- and 2.0-fold increased activity of deoxycytidine kinase (dCK), respectively. dCK catalyzes the first rate-limiting activation step of both gemcitabine and ara-C. In addition, deoxycytidine deaminase, responsible for inactivation of dFdC and ara-C, was 9.0-fold lower in H69/DAU cells. The level of thymidine kinase 2, a mitochondrial enzyme that can also phosphoryl...Continue Reading

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Citations

Jul 20, 2002·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Andries M BergmanGodefridus J Peters
Sep 19, 2009·Trends in Pharmacological Sciences·Matthew D HallMichael M Gottesman
Sep 21, 2013·Investigational New Drugs·Godefridus J PetersDeog Joong Kim
Aug 8, 2015·Nucleosides, Nucleotides & Nucleic Acids·Anna Fyrberg, Kourosh Lotfi
Jul 16, 2008·Biochimica Et Biophysica Acta·László SeresLászló Homolya
Mar 5, 2003·Pharmacological Reviews·Romano DanesiMario Del Tacca

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