Structural specificity and tumoricidal action of methyl-3,5-diiodo-4-(4'-methoxyphenoxy) benzoate (DIME)

J. Mendeleyev, L. T. Young, E. Kirsten, C. A. Vidair, A. Hakam, J. Y. Zhen, P. Bauer, K. G. Buki, E. Kun

Research output: Contribution to journalArticle

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Abstract

Seventeen homologs and analogs of methyl-3,5-diiodo-4(4'-methoxyphenoxy) benzoate (DIME), a hormonally inactive analog of thyroid hormones, have been synthesized and their antitumor activity scored by assaying their antitumorigenic effect in vivo following pretreatment of E-ras 20 cells with the drug. In vivo feeding of DIME in large doses had a similar antitumor effect on human tumor xenografts in vivo without noticeable toxicity of DIME. Inhibition of clonogenicity with MDA-MB-231 cells by DIME yielded I50 values similar to those found in tests measuring cell growth inhibition (median I50 less than 1.0 μM) The apparent ultimate signal for cytocidal action of DIME is the development of dose-dependent double strand cuts of DNA. All human tumor cells so Ear tested, with the exception of A-549 cells (lung cancer), show high sensitivity to DIME (I50 1.0 μM or below), The partially refractory behavior of A-549 cells to DIME is due to the presence of an esterase that cleaves the methyl ester group of DIME. Other tumor cells have negligible esterase activity, while such activity in homogenates of normal mouse tissues is high. Cells in culture take up DIME and the magnitude of uptake parallels drug sensitivity to DIME. Extrapolation from the correlations between drug efficacy, drug uptake, esterase activity and the absence of significant in vivo toxicity of DIME point to uptake of DIME by cells in culture but not by normal cells operating in intact organs in vivo. In contrast, tumor cells in vivo take up DIME and succumb to its cytocidal action just like cells in culture.

Original languageEnglish
Pages (from-to)689-695
Number of pages7
JournalInternational Journal of Oncology
Volume10
Issue number4
Publication statusPublished - 1997

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Esterases
Cell Culture Techniques
Pharmaceutical Preparations
Neoplasms
methyl 3,5-diiodo-4-(4'-methoxyphenoxy)benzoate
Thyroid Hormones
Heterografts
Ear
Lung Neoplasms
Esters
DNA
Growth
Inhibition (Psychology)

Keywords

  • Methyl-3,5-diiodo-4-(4'-methoxyphenoxy) benzoate (DIME)
  • Tumoricidal action

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mendeleyev, J., Young, L. T., Kirsten, E., Vidair, C. A., Hakam, A., Zhen, J. Y., ... Kun, E. (1997). Structural specificity and tumoricidal action of methyl-3,5-diiodo-4-(4'-methoxyphenoxy) benzoate (DIME). International Journal of Oncology, 10(4), 689-695.

Structural specificity and tumoricidal action of methyl-3,5-diiodo-4-(4'-methoxyphenoxy) benzoate (DIME). / Mendeleyev, J.; Young, L. T.; Kirsten, E.; Vidair, C. A.; Hakam, A.; Zhen, J. Y.; Bauer, P.; Buki, K. G.; Kun, E.

In: International Journal of Oncology, Vol. 10, No. 4, 1997, p. 689-695.

Research output: Contribution to journalArticle

Mendeleyev, J, Young, LT, Kirsten, E, Vidair, CA, Hakam, A, Zhen, JY, Bauer, P, Buki, KG & Kun, E 1997, 'Structural specificity and tumoricidal action of methyl-3,5-diiodo-4-(4'-methoxyphenoxy) benzoate (DIME)', International Journal of Oncology, vol. 10, no. 4, pp. 689-695.
Mendeleyev J, Young LT, Kirsten E, Vidair CA, Hakam A, Zhen JY et al. Structural specificity and tumoricidal action of methyl-3,5-diiodo-4-(4'-methoxyphenoxy) benzoate (DIME). International Journal of Oncology. 1997;10(4):689-695.
Mendeleyev, J. ; Young, L. T. ; Kirsten, E. ; Vidair, C. A. ; Hakam, A. ; Zhen, J. Y. ; Bauer, P. ; Buki, K. G. ; Kun, E. / Structural specificity and tumoricidal action of methyl-3,5-diiodo-4-(4'-methoxyphenoxy) benzoate (DIME). In: International Journal of Oncology. 1997 ; Vol. 10, No. 4. pp. 689-695.
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abstract = "Seventeen homologs and analogs of methyl-3,5-diiodo-4(4'-methoxyphenoxy) benzoate (DIME), a hormonally inactive analog of thyroid hormones, have been synthesized and their antitumor activity scored by assaying their antitumorigenic effect in vivo following pretreatment of E-ras 20 cells with the drug. In vivo feeding of DIME in large doses had a similar antitumor effect on human tumor xenografts in vivo without noticeable toxicity of DIME. Inhibition of clonogenicity with MDA-MB-231 cells by DIME yielded I50 values similar to those found in tests measuring cell growth inhibition (median I50 less than 1.0 μM) The apparent ultimate signal for cytocidal action of DIME is the development of dose-dependent double strand cuts of DNA. All human tumor cells so Ear tested, with the exception of A-549 cells (lung cancer), show high sensitivity to DIME (I50 1.0 μM or below), The partially refractory behavior of A-549 cells to DIME is due to the presence of an esterase that cleaves the methyl ester group of DIME. Other tumor cells have negligible esterase activity, while such activity in homogenates of normal mouse tissues is high. Cells in culture take up DIME and the magnitude of uptake parallels drug sensitivity to DIME. Extrapolation from the correlations between drug efficacy, drug uptake, esterase activity and the absence of significant in vivo toxicity of DIME point to uptake of DIME by cells in culture but not by normal cells operating in intact organs in vivo. In contrast, tumor cells in vivo take up DIME and succumb to its cytocidal action just like cells in culture.",
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