Collateral sensitivity to gemcitabine (2 ',2 ' -difluorodeoxycytidine) andcytosine arabinoside of daunorubicin- and VM-26-resistant variants of human small cell lung cancer cell lines
Am. Bergman et al., Collateral sensitivity to gemcitabine (2 ',2 ' -difluorodeoxycytidine) andcytosine arabinoside of daunorubicin- and VM-26-resistant variants of human small cell lung cancer cell lines, BIOCH PHARM, 61(11), 2001, pp. 1401-1408
Multidrug resistance (MDR), characterized by a cross-resistance to many nat
ural toxin-related compounds, may be caused either by overexpression of a d
rug efflux pump such as P-glycoprotein, (P-gP), multidrug resistance protei
ns 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 alt
ered topoisomerase MDR (at-MDR). However, human small cell lung carcinoma (
SCLC) cell lines showed a collateral sensitivity to 2',2'-difluorodeoxycyti
dine (gemcitabine, dFdC) and1-beta -D-arabinofuranosylcytosine (ara-C). H69
/DAU, a daunorubicin (DAU)-resistant variant of H69 with a P-gP overexpress
ion, and NYH/VM, a VM-26 (teniposide)-resistant variant of NYH with an at-M
DR, were both 2-fold more sensitive to,gemcitabine and 7- and 2-fold more s
ensitive to ara-C, respectively. MDR variants had a 4.3- and 2.0-fold incre
ased activity of deoxycytidine kinase (dCK), respectively, dCK catalyzes th
e first rate-limiting activation step of both gemcitabine and ara-C. In add
ition, deoxycytidine deaminase, responsible for inactivation of dFdC and ar
a-C, was 9.0-fold lower in H69/DAU cells. The level of thymidine kinase 2,
a mitochondrial enzyme that can also phosphorylate deoxycytidine and gemcit
abine, was not significantly different between the variants. These differen
ces most likely caused an increased accumulation of the active metabolites
(dFdCTP, 2.1- and 1.6-fold in NYH/VM and H69/DAU cells, respectively) and o
f ara-CTP (1.3-fold in NYH/VM cells). Ara-CTP accumulation was not detectab
le in either H69 variant. The pools of all ribonucleoside and deoxyribonucl
eoside triphosphates were at least 3- to 4-fold higher in the NYH variants
compared to the H69 variants; for dCTP and dGTP this difference was even la
rger. The higher ribonucleotide pools might explain the > 10-fold higher ac
cumulation of dFdCTP in NYH compared to H69 variants. Since dCTP is low, H6
9 cells might not need a high ara-CTP accumulation to inhibit DNA polymeras
e. This might be related to the lack of ara-CTP in H69 variants. In additio
n, the increased CTP, ATP, and UTP pools in the MDR variants might explain
the increased ara-CTP and dFdCTP accumulation. In conclusion, the MDR varia
nts of the human SCLC cell lines were collaterally sensitive due to an incr
eased dCK activity, and consequently an increased ara-CTP and dFdCTP accumu
lation. (C) 2001 Elsevier Science Inc. All rights reserved.