Interferon augments the cytotoxicity of hydroxyurea without enhancing its activity against the M2 subunit of ribonucleotide reductase: Effects in wild-type and resistant human colon cancer cells

Scott Wadler, Robert Horowitz, Jie Rao, Xun Mao, Kathie Schlesinger, Edward L. Schwartz

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15 Citations (Scopus)

Abstract

The effects of prolonged exposure to the ribonucleotide reductase (RR) inhibitor, hydroxyurea (HU), were assessed in the presence or absence of recombinant interferon alfa-2a (IFN) in wild-type human colon cancer cells (HT-29) and variants expressing low-level resistance to HU (R200). IFN at nontoxic concentrations decreased the IC50 of HU from 368 μM to 215 μM (P < 0.01) in wild-type cells, but not in the resistant variants. Potential cellular targets for the HU/IFN interaction were examined. In wild-type, but not resistant cells, treatment with HU at clinically achievable concentrations (1000 μM) resulted in rapid early inhibition of RR activity between 4 and 24 h after treatment with a maximal decrease of 65% at 12 h, decreases in cellular levels of dATP, dCTP and dGTP by 50-90% over the same time course, and a two- to fourfold increase in the level of mRNA for both the M1 and M2 subunits of RR, at 24, but not between 1 and 4 h, which probably represents a response to the earlier decrease in RR activity. IFN at a clinically achievable concentration (500 U/ml) failed to augment the effects of HU on RR protein, RR mRNA levels or RR enzyme activity in either the wild-type or resistant cells, suggesting that the mechanism by which IFN augments the effects of HU in the wild-type cells is independent of the effects of HU on M2.

Original languageEnglish (US)
Pages (from-to)522-528
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume38
Issue number6
DOIs
StatePublished - 1996

Fingerprint

Hydroxyurea
Cytotoxicity
Ribonucleotide Reductases
Colonic Neoplasms
Interferons
Cells
HT29 Cells
Messenger RNA
ribonucleotide reductase M2
Enzyme activity
Inhibitory Concentration 50
Enzymes

Keywords

  • Colon cancer
  • Drug resistance
  • Hydroxyurea
  • Interferon alfa-2a
  • Ribonucleotide reductase

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

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title = "Interferon augments the cytotoxicity of hydroxyurea without enhancing its activity against the M2 subunit of ribonucleotide reductase: Effects in wild-type and resistant human colon cancer cells",
abstract = "The effects of prolonged exposure to the ribonucleotide reductase (RR) inhibitor, hydroxyurea (HU), were assessed in the presence or absence of recombinant interferon alfa-2a (IFN) in wild-type human colon cancer cells (HT-29) and variants expressing low-level resistance to HU (R200). IFN at nontoxic concentrations decreased the IC50 of HU from 368 μM to 215 μM (P < 0.01) in wild-type cells, but not in the resistant variants. Potential cellular targets for the HU/IFN interaction were examined. In wild-type, but not resistant cells, treatment with HU at clinically achievable concentrations (1000 μM) resulted in rapid early inhibition of RR activity between 4 and 24 h after treatment with a maximal decrease of 65{\%} at 12 h, decreases in cellular levels of dATP, dCTP and dGTP by 50-90{\%} over the same time course, and a two- to fourfold increase in the level of mRNA for both the M1 and M2 subunits of RR, at 24, but not between 1 and 4 h, which probably represents a response to the earlier decrease in RR activity. IFN at a clinically achievable concentration (500 U/ml) failed to augment the effects of HU on RR protein, RR mRNA levels or RR enzyme activity in either the wild-type or resistant cells, suggesting that the mechanism by which IFN augments the effects of HU in the wild-type cells is independent of the effects of HU on M2.",
keywords = "Colon cancer, Drug resistance, Hydroxyurea, Interferon alfa-2a, Ribonucleotide reductase",
author = "Scott Wadler and Robert Horowitz and Jie Rao and Xun Mao and Kathie Schlesinger and Schwartz, {Edward L.}",
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T1 - Interferon augments the cytotoxicity of hydroxyurea without enhancing its activity against the M2 subunit of ribonucleotide reductase

T2 - Effects in wild-type and resistant human colon cancer cells

AU - Wadler, Scott

AU - Horowitz, Robert

AU - Rao, Jie

AU - Mao, Xun

AU - Schlesinger, Kathie

AU - Schwartz, Edward L.

PY - 1996

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N2 - The effects of prolonged exposure to the ribonucleotide reductase (RR) inhibitor, hydroxyurea (HU), were assessed in the presence or absence of recombinant interferon alfa-2a (IFN) in wild-type human colon cancer cells (HT-29) and variants expressing low-level resistance to HU (R200). IFN at nontoxic concentrations decreased the IC50 of HU from 368 μM to 215 μM (P < 0.01) in wild-type cells, but not in the resistant variants. Potential cellular targets for the HU/IFN interaction were examined. In wild-type, but not resistant cells, treatment with HU at clinically achievable concentrations (1000 μM) resulted in rapid early inhibition of RR activity between 4 and 24 h after treatment with a maximal decrease of 65% at 12 h, decreases in cellular levels of dATP, dCTP and dGTP by 50-90% over the same time course, and a two- to fourfold increase in the level of mRNA for both the M1 and M2 subunits of RR, at 24, but not between 1 and 4 h, which probably represents a response to the earlier decrease in RR activity. IFN at a clinically achievable concentration (500 U/ml) failed to augment the effects of HU on RR protein, RR mRNA levels or RR enzyme activity in either the wild-type or resistant cells, suggesting that the mechanism by which IFN augments the effects of HU in the wild-type cells is independent of the effects of HU on M2.

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