ICI D1694 and idoxuridine: A synergistic antitumor combination

Josie Pressacco, David W. Hedley, Charles Erlichman

Research output: Contribution to journalArticle

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Abstract

The cytotoxicity of idoxuridine (IdUrd), a thymidine analogue, and ICI D1694 (D1694), a folate-based thymidylate synthase (TS) inhibitor, were examined individually and in combination in two human tumor cell lines. MGH- U1 bladder cancer and HCT-8 colon cancer cells were grown as monolayer cultures with and without thymidine. The cytotoxicity of these agents alone and in combination were determined using normal human bone marrow colony- forming unit, granulocyte-macrophage (CFU-GM) as a surrogate for myelosuppression in vivo. Thymidylate synthase inhibition, IdUrd incorporation into DNA, and DNA single-strand breaks were measured in each cell line and related to cytotoxicity. The cytotoxicity of a 24-h exposure to IdUrd or D1694 increased with drug concentration in each cell line. The drug concentrations producing 50% and 10% clonogenic survival in MGH-U1 cells, respectively, were 0.006 and 0.009 μM for D1694 and 13.0 and 81.0 μM for IdUrd. Those for HCT-8 cells, respectively, were 0.009 and 0.018 μM for D1694 and 7.5 and 20.5 μM for IdUrd. The cytotoxicity of IdUrd combined with D1694 was synergistic in both MGH-U1 and HCT-8 cells as determined by median- effect analysis. The addition of thymidine at concentrations of 0.1, 0.3, and 1.0 μM to the culture medium did not decrease the cytotoxicity of D1694 in either tumor cell line. TS inhibition using the whole cell assay was observed with only D1694, producing 50% inhibition of TS activity at 0.002 μM for MGH-U1 and 0.007 μM for HCT-8 cells. IdUrd did not inhibit TS activity, nor did it enhance the TS inhibitory effects of D1694. The incorporation of IdUrd into DNA increased with increasing concentrations of D1694. This increased DNA incorporation correlated with the increase in DNA single-strand breaks. DNA single-strand breaks paralleled cytotoxicity. CFU-GM survival, exposed to the same drug concentrations as those used in the tumor cell lines, revealed that the therapeutic index was greater for the combination than for either agent alone. These findings suggest that IdUrd plus D1694 is a promising new drug combination, which may have a favorable therapeutic index in vivo.

Original languageEnglish (US)
Pages (from-to)3772-3778
Number of pages7
JournalCancer Research
Volume54
Issue number14
StatePublished - Jul 15 1994
Externally publishedYes

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Idoxuridine
Thymidylate Synthase
Single-Stranded DNA Breaks
Tumor Cell Line
Thymidine
Granulocyte-Macrophage Progenitor Cells
DNA
raltitrexed
Pharmaceutical Preparations
Cell Line
Drug Combinations
Folic Acid
Urinary Bladder Neoplasms
Colonic Neoplasms
Culture Media
Bone Marrow

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Pressacco, J., Hedley, D. W., & Erlichman, C. (1994). ICI D1694 and idoxuridine: A synergistic antitumor combination. Cancer Research, 54(14), 3772-3778.

ICI D1694 and idoxuridine : A synergistic antitumor combination. / Pressacco, Josie; Hedley, David W.; Erlichman, Charles.

In: Cancer Research, Vol. 54, No. 14, 15.07.1994, p. 3772-3778.

Research output: Contribution to journalArticle

Pressacco, J, Hedley, DW & Erlichman, C 1994, 'ICI D1694 and idoxuridine: A synergistic antitumor combination', Cancer Research, vol. 54, no. 14, pp. 3772-3778.
Pressacco J, Hedley DW, Erlichman C. ICI D1694 and idoxuridine: A synergistic antitumor combination. Cancer Research. 1994 Jul 15;54(14):3772-3778.
Pressacco, Josie ; Hedley, David W. ; Erlichman, Charles. / ICI D1694 and idoxuridine : A synergistic antitumor combination. In: Cancer Research. 1994 ; Vol. 54, No. 14. pp. 3772-3778.
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abstract = "The cytotoxicity of idoxuridine (IdUrd), a thymidine analogue, and ICI D1694 (D1694), a folate-based thymidylate synthase (TS) inhibitor, were examined individually and in combination in two human tumor cell lines. MGH- U1 bladder cancer and HCT-8 colon cancer cells were grown as monolayer cultures with and without thymidine. The cytotoxicity of these agents alone and in combination were determined using normal human bone marrow colony- forming unit, granulocyte-macrophage (CFU-GM) as a surrogate for myelosuppression in vivo. Thymidylate synthase inhibition, IdUrd incorporation into DNA, and DNA single-strand breaks were measured in each cell line and related to cytotoxicity. The cytotoxicity of a 24-h exposure to IdUrd or D1694 increased with drug concentration in each cell line. The drug concentrations producing 50{\%} and 10{\%} clonogenic survival in MGH-U1 cells, respectively, were 0.006 and 0.009 μM for D1694 and 13.0 and 81.0 μM for IdUrd. Those for HCT-8 cells, respectively, were 0.009 and 0.018 μM for D1694 and 7.5 and 20.5 μM for IdUrd. The cytotoxicity of IdUrd combined with D1694 was synergistic in both MGH-U1 and HCT-8 cells as determined by median- effect analysis. The addition of thymidine at concentrations of 0.1, 0.3, and 1.0 μM to the culture medium did not decrease the cytotoxicity of D1694 in either tumor cell line. TS inhibition using the whole cell assay was observed with only D1694, producing 50{\%} inhibition of TS activity at 0.002 μM for MGH-U1 and 0.007 μM for HCT-8 cells. IdUrd did not inhibit TS activity, nor did it enhance the TS inhibitory effects of D1694. The incorporation of IdUrd into DNA increased with increasing concentrations of D1694. This increased DNA incorporation correlated with the increase in DNA single-strand breaks. DNA single-strand breaks paralleled cytotoxicity. CFU-GM survival, exposed to the same drug concentrations as those used in the tumor cell lines, revealed that the therapeutic index was greater for the combination than for either agent alone. These findings suggest that IdUrd plus D1694 is a promising new drug combination, which may have a favorable therapeutic index in vivo.",
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