Quantitation of synergism of arabinosylcytosine and cladribine against the growth of arabinosylcytosine-resistant human lymphoid cells

Tieran Han, Marilyn Fernandez, Ting Chao Chou, Ram P. Agarwal

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

This report presents a quantitative analysis of the synergistic interaction of arabinosylcytosine (araC) and cladribine (CdA) in human H9-lymphoid cell lines sensitive and resistant to araC (H9-araC cells). H9-araC cells obtained by cultivation of H9 cells in the presence of 0.5 μM arabinosylcytosine (araC) had lower deoxycytidine kinase (dCK) than the parental cell line. The IC 50 values of araC and CdA calculated by using median-effect analysis and CalcuSyn software were: 0.55 μM and 1.16 μM for CdA and 0.0058 μM and 3.5 μM for araC in H9 and H9-araC cells, respectively. These values were reduced to 0.10 μM and 0.38 μM for CdA and to 0.004 μM and to 0.77 μM for araC when the drugs were used in combination. Computerized simulation of dose reduction index (DRI) indicated that at 50-99% growth inhibition levels, the doses of araC could be reduced by 2.0 to 11.9-fold and 2.9 to 5.3-fold and the doses of CdA by 5.9 and 183.7-fold and 3.1 to 164.8-fold in H9 and H9-araC cells, respectively, when the drugs are used in combination. Assessment by combination index (CI) analysis showed that the combination exhibited moderate to strong synergistic lympho-cytotoxic effects. CdA metabolic studies (influx and activation) in the presence of deoxyadenosine, deoxycytidine, or araC suggested that CdA enters cells by a deoxyadenosine-inhibitable transport system, which is different than that of araC and deoxycytidine transport system. Thus, in addition to the known mechanisms, other mechanisms might be involved in the metabolism of CdA. The demonstration that araC and CdA combinations exert synergistic cytotoxicity even in the resistant cells raises hope that such a combination may be useful in tumors that were found resistant to these drugs.

Original languageEnglish
Pages (from-to)609-616
Number of pages8
JournalJournal of Cancer Research and Clinical Oncology
Volume131
Issue number9
DOIs
StatePublished - Sep 1 2005
Externally publishedYes

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Cladribine
Cytarabine
Lymphocytes
Growth
Deoxycytidine
Deoxycytidine Kinase
Pharmaceutical Preparations
Cell Line

Keywords

  • Arabinosylcytosine
  • Arabinosylcytosine resistance
  • Cladribine
  • Dose reduction index
  • Synergistic cytotoxicity

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Quantitation of synergism of arabinosylcytosine and cladribine against the growth of arabinosylcytosine-resistant human lymphoid cells. / Han, Tieran; Fernandez, Marilyn; Chou, Ting Chao; Agarwal, Ram P.

In: Journal of Cancer Research and Clinical Oncology, Vol. 131, No. 9, 01.09.2005, p. 609-616.

Research output: Contribution to journalArticle

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abstract = "This report presents a quantitative analysis of the synergistic interaction of arabinosylcytosine (araC) and cladribine (CdA) in human H9-lymphoid cell lines sensitive and resistant to araC (H9-araC cells). H9-araC cells obtained by cultivation of H9 cells in the presence of 0.5 μM arabinosylcytosine (araC) had lower deoxycytidine kinase (dCK) than the parental cell line. The IC 50 values of araC and CdA calculated by using median-effect analysis and CalcuSyn software were: 0.55 μM and 1.16 μM for CdA and 0.0058 μM and 3.5 μM for araC in H9 and H9-araC cells, respectively. These values were reduced to 0.10 μM and 0.38 μM for CdA and to 0.004 μM and to 0.77 μM for araC when the drugs were used in combination. Computerized simulation of dose reduction index (DRI) indicated that at 50-99{\%} growth inhibition levels, the doses of araC could be reduced by 2.0 to 11.9-fold and 2.9 to 5.3-fold and the doses of CdA by 5.9 and 183.7-fold and 3.1 to 164.8-fold in H9 and H9-araC cells, respectively, when the drugs are used in combination. Assessment by combination index (CI) analysis showed that the combination exhibited moderate to strong synergistic lympho-cytotoxic effects. CdA metabolic studies (influx and activation) in the presence of deoxyadenosine, deoxycytidine, or araC suggested that CdA enters cells by a deoxyadenosine-inhibitable transport system, which is different than that of araC and deoxycytidine transport system. Thus, in addition to the known mechanisms, other mechanisms might be involved in the metabolism of CdA. The demonstration that araC and CdA combinations exert synergistic cytotoxicity even in the resistant cells raises hope that such a combination may be useful in tumors that were found resistant to these drugs.",
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AU - Agarwal, Ram P.

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N2 - This report presents a quantitative analysis of the synergistic interaction of arabinosylcytosine (araC) and cladribine (CdA) in human H9-lymphoid cell lines sensitive and resistant to araC (H9-araC cells). H9-araC cells obtained by cultivation of H9 cells in the presence of 0.5 μM arabinosylcytosine (araC) had lower deoxycytidine kinase (dCK) than the parental cell line. The IC 50 values of araC and CdA calculated by using median-effect analysis and CalcuSyn software were: 0.55 μM and 1.16 μM for CdA and 0.0058 μM and 3.5 μM for araC in H9 and H9-araC cells, respectively. These values were reduced to 0.10 μM and 0.38 μM for CdA and to 0.004 μM and to 0.77 μM for araC when the drugs were used in combination. Computerized simulation of dose reduction index (DRI) indicated that at 50-99% growth inhibition levels, the doses of araC could be reduced by 2.0 to 11.9-fold and 2.9 to 5.3-fold and the doses of CdA by 5.9 and 183.7-fold and 3.1 to 164.8-fold in H9 and H9-araC cells, respectively, when the drugs are used in combination. Assessment by combination index (CI) analysis showed that the combination exhibited moderate to strong synergistic lympho-cytotoxic effects. CdA metabolic studies (influx and activation) in the presence of deoxyadenosine, deoxycytidine, or araC suggested that CdA enters cells by a deoxyadenosine-inhibitable transport system, which is different than that of araC and deoxycytidine transport system. Thus, in addition to the known mechanisms, other mechanisms might be involved in the metabolism of CdA. The demonstration that araC and CdA combinations exert synergistic cytotoxicity even in the resistant cells raises hope that such a combination may be useful in tumors that were found resistant to these drugs.

AB - This report presents a quantitative analysis of the synergistic interaction of arabinosylcytosine (araC) and cladribine (CdA) in human H9-lymphoid cell lines sensitive and resistant to araC (H9-araC cells). H9-araC cells obtained by cultivation of H9 cells in the presence of 0.5 μM arabinosylcytosine (araC) had lower deoxycytidine kinase (dCK) than the parental cell line. The IC 50 values of araC and CdA calculated by using median-effect analysis and CalcuSyn software were: 0.55 μM and 1.16 μM for CdA and 0.0058 μM and 3.5 μM for araC in H9 and H9-araC cells, respectively. These values were reduced to 0.10 μM and 0.38 μM for CdA and to 0.004 μM and to 0.77 μM for araC when the drugs were used in combination. Computerized simulation of dose reduction index (DRI) indicated that at 50-99% growth inhibition levels, the doses of araC could be reduced by 2.0 to 11.9-fold and 2.9 to 5.3-fold and the doses of CdA by 5.9 and 183.7-fold and 3.1 to 164.8-fold in H9 and H9-araC cells, respectively, when the drugs are used in combination. Assessment by combination index (CI) analysis showed that the combination exhibited moderate to strong synergistic lympho-cytotoxic effects. CdA metabolic studies (influx and activation) in the presence of deoxyadenosine, deoxycytidine, or araC suggested that CdA enters cells by a deoxyadenosine-inhibitable transport system, which is different than that of araC and deoxycytidine transport system. Thus, in addition to the known mechanisms, other mechanisms might be involved in the metabolism of CdA. The demonstration that araC and CdA combinations exert synergistic cytotoxicity even in the resistant cells raises hope that such a combination may be useful in tumors that were found resistant to these drugs.

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KW - Dose reduction index

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