Use of 5-trifluoromethyldeoxycytidine and tetrahydrouridine to circumvent catabolism and exploit high levels of cytidine deaminase in tumors to achieve DNA- and target-directed therapies

J. A. Mekras, A. Boothman, S. B. Greer

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

5-Trifluoromethyldeoxycytidine (F3methyl-dCyd), when coadministered with tetrahydrouridine (H4Urd), surpasses the efficacy of 5-trifluorothymidine and 5-trifluormethyl-2' deoxycytidine when administered alone as demonstrated with adenocarcinoma 755 and Lewis lung carcinoma as solid tumors implanted in C57BL x DBA/2 F1 mice. It appears that the reason for the heightened efficacy of F3methyl-dCyd, when coadministered with low concentrations of H4Urd, is decreased systemic deamination and subsequent systemic catabolism by pyrimidine nucleoside phosphorylase, which do not act on deoxycytidine and its analogues. Furthermore, the elevated levels of cytidine deaminase in these mouse tumors may result in selective conversion of F3methyl-dCyd to 5-trifluorothymidine at the tumor site. This suggests an approach to the treatment of human tumors possessing elevated levels of cytidine deaminase such as certain leukemias, bronchogenic carcinoma of the lung, adenocarcinomas of the colon and rectum, astrocytomas, and certain tumors which are refractory to chemotherapy with 1-β-arabinofuranosylcytosine. In contrast to fluorinated pyrimidines in current use, F3methyl-dCyd + H4Urd potentially allows an exclusive DNA-, rather than both a DNA- and RNA-, directed approach. The major mechanism of the antitumor activity of F3methyl-dCyd appears to be via inhibition by 5-trifluorothymidine-5'-monophosphate of thymidylate synthetase, the target enzyme of fluoropyrimidine analogues in current use. However, the established and potential differences in the mode of action, anabolism, nature of incorporation into DNA, repair and cofactor requirements of F3methyl-dCyd and its anabolites, compared to that of the commonly utilized fluorinated pyrimidines, indicate that F3methyl-dCyd + H4Urd is a novel combination of agents. In comparative studies with Lewis lung carcinoma, F3methyl-dCyd (+ H4Urd) was shown to surpass the efficacies of 5-fluorouracil and 5-fluorodeoxyuridine and to be essentially equal in efficacy to 5-fluorodeoxycytidine (+ H4Urd). The optimum established protocol against Lewis lung carcinoma is F3methyl-dCyd, 175 mg/kg, + H4Urd, 25 mg/kg, once per day for 7 days. Studies utilizing high concentrations of H4Urd coadministered with F3methyl-dCyd indicate that the major pathway of tumor inhibition is via conversion of F3methyl-dCyd to 5-trifluorothymidine in view of the fact that tumor inhibition diminishes at doses of H4Urd which result in extensive (93%) inhibition of tumor cytidine deaminase. The most efficacious coadministered doses of H4Urd (25 or 50 mg/kg) result in greater than 90% inhibition of the cytidine deaminase of serum, spleen, and liver and 65 and 55% inhibition of bone marrow and intestine, respectively; whereas, tumor cytidine deaminase is only moderately inhibited (33%). These findings relate to a new approach in the chemotherapy of cancer: tumor-specific activation coupled with protection of normal tissues by using modulating concentrations of an inhibitor of a converting (or activating) enzyme. This strategy magnifies the intrinsic differences in enzyme levels between normal and tumor tissue, thereby allowing heightened selectivity.

Original languageEnglish
Pages (from-to)5270-5280
Number of pages11
JournalCancer Research
Volume45
Issue number11 I
StatePublished - Dec 1 1985
Externally publishedYes

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Tetrahydrouridine
Cytidine Deaminase
DNA
Trifluridine
Neoplasms
Lewis Lung Carcinoma
Therapeutics
Pyrimidines
Deoxycytidine
Pyrimidine Phosphorylases
Enzymes
Floxuridine
Drug Therapy
Thymidylate Synthase
Deamination
Bronchogenic Carcinoma
Cytarabine
Astrocytoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Use of 5-trifluoromethyldeoxycytidine and tetrahydrouridine to circumvent catabolism and exploit high levels of cytidine deaminase in tumors to achieve DNA- and target-directed therapies. / Mekras, J. A.; Boothman, A.; Greer, S. B.

In: Cancer Research, Vol. 45, No. 11 I, 01.12.1985, p. 5270-5280.

Research output: Contribution to journalArticle

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abstract = "5-Trifluoromethyldeoxycytidine (F3methyl-dCyd), when coadministered with tetrahydrouridine (H4Urd), surpasses the efficacy of 5-trifluorothymidine and 5-trifluormethyl-2' deoxycytidine when administered alone as demonstrated with adenocarcinoma 755 and Lewis lung carcinoma as solid tumors implanted in C57BL x DBA/2 F1 mice. It appears that the reason for the heightened efficacy of F3methyl-dCyd, when coadministered with low concentrations of H4Urd, is decreased systemic deamination and subsequent systemic catabolism by pyrimidine nucleoside phosphorylase, which do not act on deoxycytidine and its analogues. Furthermore, the elevated levels of cytidine deaminase in these mouse tumors may result in selective conversion of F3methyl-dCyd to 5-trifluorothymidine at the tumor site. This suggests an approach to the treatment of human tumors possessing elevated levels of cytidine deaminase such as certain leukemias, bronchogenic carcinoma of the lung, adenocarcinomas of the colon and rectum, astrocytomas, and certain tumors which are refractory to chemotherapy with 1-β-arabinofuranosylcytosine. In contrast to fluorinated pyrimidines in current use, F3methyl-dCyd + H4Urd potentially allows an exclusive DNA-, rather than both a DNA- and RNA-, directed approach. The major mechanism of the antitumor activity of F3methyl-dCyd appears to be via inhibition by 5-trifluorothymidine-5'-monophosphate of thymidylate synthetase, the target enzyme of fluoropyrimidine analogues in current use. However, the established and potential differences in the mode of action, anabolism, nature of incorporation into DNA, repair and cofactor requirements of F3methyl-dCyd and its anabolites, compared to that of the commonly utilized fluorinated pyrimidines, indicate that F3methyl-dCyd + H4Urd is a novel combination of agents. In comparative studies with Lewis lung carcinoma, F3methyl-dCyd (+ H4Urd) was shown to surpass the efficacies of 5-fluorouracil and 5-fluorodeoxyuridine and to be essentially equal in efficacy to 5-fluorodeoxycytidine (+ H4Urd). The optimum established protocol against Lewis lung carcinoma is F3methyl-dCyd, 175 mg/kg, + H4Urd, 25 mg/kg, once per day for 7 days. Studies utilizing high concentrations of H4Urd coadministered with F3methyl-dCyd indicate that the major pathway of tumor inhibition is via conversion of F3methyl-dCyd to 5-trifluorothymidine in view of the fact that tumor inhibition diminishes at doses of H4Urd which result in extensive (93{\%}) inhibition of tumor cytidine deaminase. The most efficacious coadministered doses of H4Urd (25 or 50 mg/kg) result in greater than 90{\%} inhibition of the cytidine deaminase of serum, spleen, and liver and 65 and 55{\%} inhibition of bone marrow and intestine, respectively; whereas, tumor cytidine deaminase is only moderately inhibited (33{\%}). These findings relate to a new approach in the chemotherapy of cancer: tumor-specific activation coupled with protection of normal tissues by using modulating concentrations of an inhibitor of a converting (or activating) enzyme. This strategy magnifies the intrinsic differences in enzyme levels between normal and tumor tissue, thereby allowing heightened selectivity.",
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T1 - Use of 5-trifluoromethyldeoxycytidine and tetrahydrouridine to circumvent catabolism and exploit high levels of cytidine deaminase in tumors to achieve DNA- and target-directed therapies

AU - Mekras, J. A.

AU - Boothman, A.

AU - Greer, S. B.

PY - 1985/12/1

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N2 - 5-Trifluoromethyldeoxycytidine (F3methyl-dCyd), when coadministered with tetrahydrouridine (H4Urd), surpasses the efficacy of 5-trifluorothymidine and 5-trifluormethyl-2' deoxycytidine when administered alone as demonstrated with adenocarcinoma 755 and Lewis lung carcinoma as solid tumors implanted in C57BL x DBA/2 F1 mice. It appears that the reason for the heightened efficacy of F3methyl-dCyd, when coadministered with low concentrations of H4Urd, is decreased systemic deamination and subsequent systemic catabolism by pyrimidine nucleoside phosphorylase, which do not act on deoxycytidine and its analogues. Furthermore, the elevated levels of cytidine deaminase in these mouse tumors may result in selective conversion of F3methyl-dCyd to 5-trifluorothymidine at the tumor site. This suggests an approach to the treatment of human tumors possessing elevated levels of cytidine deaminase such as certain leukemias, bronchogenic carcinoma of the lung, adenocarcinomas of the colon and rectum, astrocytomas, and certain tumors which are refractory to chemotherapy with 1-β-arabinofuranosylcytosine. In contrast to fluorinated pyrimidines in current use, F3methyl-dCyd + H4Urd potentially allows an exclusive DNA-, rather than both a DNA- and RNA-, directed approach. The major mechanism of the antitumor activity of F3methyl-dCyd appears to be via inhibition by 5-trifluorothymidine-5'-monophosphate of thymidylate synthetase, the target enzyme of fluoropyrimidine analogues in current use. However, the established and potential differences in the mode of action, anabolism, nature of incorporation into DNA, repair and cofactor requirements of F3methyl-dCyd and its anabolites, compared to that of the commonly utilized fluorinated pyrimidines, indicate that F3methyl-dCyd + H4Urd is a novel combination of agents. In comparative studies with Lewis lung carcinoma, F3methyl-dCyd (+ H4Urd) was shown to surpass the efficacies of 5-fluorouracil and 5-fluorodeoxyuridine and to be essentially equal in efficacy to 5-fluorodeoxycytidine (+ H4Urd). The optimum established protocol against Lewis lung carcinoma is F3methyl-dCyd, 175 mg/kg, + H4Urd, 25 mg/kg, once per day for 7 days. Studies utilizing high concentrations of H4Urd coadministered with F3methyl-dCyd indicate that the major pathway of tumor inhibition is via conversion of F3methyl-dCyd to 5-trifluorothymidine in view of the fact that tumor inhibition diminishes at doses of H4Urd which result in extensive (93%) inhibition of tumor cytidine deaminase. The most efficacious coadministered doses of H4Urd (25 or 50 mg/kg) result in greater than 90% inhibition of the cytidine deaminase of serum, spleen, and liver and 65 and 55% inhibition of bone marrow and intestine, respectively; whereas, tumor cytidine deaminase is only moderately inhibited (33%). These findings relate to a new approach in the chemotherapy of cancer: tumor-specific activation coupled with protection of normal tissues by using modulating concentrations of an inhibitor of a converting (or activating) enzyme. This strategy magnifies the intrinsic differences in enzyme levels between normal and tumor tissue, thereby allowing heightened selectivity.

AB - 5-Trifluoromethyldeoxycytidine (F3methyl-dCyd), when coadministered with tetrahydrouridine (H4Urd), surpasses the efficacy of 5-trifluorothymidine and 5-trifluormethyl-2' deoxycytidine when administered alone as demonstrated with adenocarcinoma 755 and Lewis lung carcinoma as solid tumors implanted in C57BL x DBA/2 F1 mice. It appears that the reason for the heightened efficacy of F3methyl-dCyd, when coadministered with low concentrations of H4Urd, is decreased systemic deamination and subsequent systemic catabolism by pyrimidine nucleoside phosphorylase, which do not act on deoxycytidine and its analogues. Furthermore, the elevated levels of cytidine deaminase in these mouse tumors may result in selective conversion of F3methyl-dCyd to 5-trifluorothymidine at the tumor site. This suggests an approach to the treatment of human tumors possessing elevated levels of cytidine deaminase such as certain leukemias, bronchogenic carcinoma of the lung, adenocarcinomas of the colon and rectum, astrocytomas, and certain tumors which are refractory to chemotherapy with 1-β-arabinofuranosylcytosine. In contrast to fluorinated pyrimidines in current use, F3methyl-dCyd + H4Urd potentially allows an exclusive DNA-, rather than both a DNA- and RNA-, directed approach. The major mechanism of the antitumor activity of F3methyl-dCyd appears to be via inhibition by 5-trifluorothymidine-5'-monophosphate of thymidylate synthetase, the target enzyme of fluoropyrimidine analogues in current use. However, the established and potential differences in the mode of action, anabolism, nature of incorporation into DNA, repair and cofactor requirements of F3methyl-dCyd and its anabolites, compared to that of the commonly utilized fluorinated pyrimidines, indicate that F3methyl-dCyd + H4Urd is a novel combination of agents. In comparative studies with Lewis lung carcinoma, F3methyl-dCyd (+ H4Urd) was shown to surpass the efficacies of 5-fluorouracil and 5-fluorodeoxyuridine and to be essentially equal in efficacy to 5-fluorodeoxycytidine (+ H4Urd). The optimum established protocol against Lewis lung carcinoma is F3methyl-dCyd, 175 mg/kg, + H4Urd, 25 mg/kg, once per day for 7 days. Studies utilizing high concentrations of H4Urd coadministered with F3methyl-dCyd indicate that the major pathway of tumor inhibition is via conversion of F3methyl-dCyd to 5-trifluorothymidine in view of the fact that tumor inhibition diminishes at doses of H4Urd which result in extensive (93%) inhibition of tumor cytidine deaminase. The most efficacious coadministered doses of H4Urd (25 or 50 mg/kg) result in greater than 90% inhibition of the cytidine deaminase of serum, spleen, and liver and 65 and 55% inhibition of bone marrow and intestine, respectively; whereas, tumor cytidine deaminase is only moderately inhibited (33%). These findings relate to a new approach in the chemotherapy of cancer: tumor-specific activation coupled with protection of normal tissues by using modulating concentrations of an inhibitor of a converting (or activating) enzyme. This strategy magnifies the intrinsic differences in enzyme levels between normal and tumor tissue, thereby allowing heightened selectivity.

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