Marked radiosensitization of cells in culture to X ray by 5-chlorodeoxycytidine coadministered with tetrahydrouridine, and inhibitors of pyrimidine biosynthesis

Liliana M. Perez, John A. Mekras, Thomas V. Briggle, Sheldon Greer

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Our approach to overcome the problem of rapid catabolism and general toxicity encountered with 5-halogenated analogues of deoxyuridine (5-bromo, chloro or iododeoxyuridine~ which has limited their use as tumor radiosensitizers, is to utilize 5-chlorodeoxycytidine (CldC with tetrahydrouridine (H4U) We propose that CIdC, co-administered with H4 is metabolized in the following manner: CldC → CIdCMP → CIdUMP → CIdUTP → DNA. All the enzymes of this pathway are elevated in many human malignant tumors and in HEp-2 cells. In X irradiation studies with HEp-2 cells, limited to 1 or 2 radiation doses, we have obtained 3.0 to 3.8 apparent dose enhancement ratios (these represent upper limits) when cells are preincubated with inhibitors of pyrimidine biosynthesis: N-(Phosphonacetyl)-L-aspartate (PALA) and 5-fluorodeoxyuridine (FdU) or 5-fluorodeoxycytidine (FdC) + H4U Optimum conditions for radiosensitization are: PALA (0.1 mg/ml) 18-20 hr prior to FdU (0.1 μM or FdC (0.02 μM + H4U (0.1 mM) followed 6 hr later by CIdC (0.1-0.2 mM) + H4U (0.1 mM) for 56-68 hr. Viabilities of 10 ± 4% to 15 ±t 1% (±S.E.) were obtained for drug-treated unirradiated cells. Enzymatic studies indicate that this toxicity may be tumor selective. CIdC + H4 alone (at these concentrations) results in 20% substitution of CIdU for thymidine in DNA (determined by HPLC analysis). Preliminary toxicity studies indicate that mice will tolerate treatment protocols involving a single dose of PALA (200 mg/kg) followed by a dose of FdU (50 mg/kg) and 3 cycles of CldC (500 mg/kg) + H4U (100 mg/kg) at 10 hour intervals, with marginal weight loss (496). In this approach we seek to obtain preferential conversion of CIdC to CIdUTP at the tumor site by taking advantage of quantitative differences in enzyme levels between tumors and normal tissues.

Original languageEnglish
Pages (from-to)1453-1458
Number of pages6
JournalInternational journal of radiation oncology, biology, physics
Volume10
Issue number8
DOIs
StatePublished - Jan 1 1984
Externally publishedYes

Fingerprint

Tetrahydrouridine
biosynthesis
pyrimidines
inhibitors
Floxuridine
aspartates
tumors
Cell Culture Techniques
X-Rays
toxicity
dosage
cells
NSC 224131
Neoplasms
x rays
Aspartic Acid
enzymes
catabolism
deoxyribonucleic acid
Idoxuridine

Keywords

  • 5-Chlorodeoxycytidine (CIdC)
  • 5-Fluorodeoxycytidine (FdC)
  • 5-Fluorodeoxyuridine (FdU)
  • Deoxycytidine kinase (dCK)
  • Deoxycytidylate deaminase (dCMPD)
  • Radlosensitization
  • Tetrahydrouridine (HU) N-(Phosphonacetyl)-L-aspartate (PALA)
  • Tumor-directed toxicity

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation

Cite this

Marked radiosensitization of cells in culture to X ray by 5-chlorodeoxycytidine coadministered with tetrahydrouridine, and inhibitors of pyrimidine biosynthesis. / Perez, Liliana M.; Mekras, John A.; Briggle, Thomas V.; Greer, Sheldon.

In: International journal of radiation oncology, biology, physics, Vol. 10, No. 8, 01.01.1984, p. 1453-1458.

Research output: Contribution to journalArticle

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abstract = "Our approach to overcome the problem of rapid catabolism and general toxicity encountered with 5-halogenated analogues of deoxyuridine (5-bromo, chloro or iododeoxyuridine~ which has limited their use as tumor radiosensitizers, is to utilize 5-chlorodeoxycytidine (CldC with tetrahydrouridine (H4U) We propose that CIdC, co-administered with H4 is metabolized in the following manner: CldC → CIdCMP → CIdUMP → CIdUTP → DNA. All the enzymes of this pathway are elevated in many human malignant tumors and in HEp-2 cells. In X irradiation studies with HEp-2 cells, limited to 1 or 2 radiation doses, we have obtained 3.0 to 3.8 apparent dose enhancement ratios (these represent upper limits) when cells are preincubated with inhibitors of pyrimidine biosynthesis: N-(Phosphonacetyl)-L-aspartate (PALA) and 5-fluorodeoxyuridine (FdU) or 5-fluorodeoxycytidine (FdC) + H4U Optimum conditions for radiosensitization are: PALA (0.1 mg/ml) 18-20 hr prior to FdU (0.1 μM or FdC (0.02 μM + H4U (0.1 mM) followed 6 hr later by CIdC (0.1-0.2 mM) + H4U (0.1 mM) for 56-68 hr. Viabilities of 10 ± 4{\%} to 15 ±t 1{\%} (±S.E.) were obtained for drug-treated unirradiated cells. Enzymatic studies indicate that this toxicity may be tumor selective. CIdC + H4 alone (at these concentrations) results in 20{\%} substitution of CIdU for thymidine in DNA (determined by HPLC analysis). Preliminary toxicity studies indicate that mice will tolerate treatment protocols involving a single dose of PALA (200 mg/kg) followed by a dose of FdU (50 mg/kg) and 3 cycles of CldC (500 mg/kg) + H4U (100 mg/kg) at 10 hour intervals, with marginal weight loss (496). In this approach we seek to obtain preferential conversion of CIdC to CIdUTP at the tumor site by taking advantage of quantitative differences in enzyme levels between tumors and normal tissues.",
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N2 - Our approach to overcome the problem of rapid catabolism and general toxicity encountered with 5-halogenated analogues of deoxyuridine (5-bromo, chloro or iododeoxyuridine~ which has limited their use as tumor radiosensitizers, is to utilize 5-chlorodeoxycytidine (CldC with tetrahydrouridine (H4U) We propose that CIdC, co-administered with H4 is metabolized in the following manner: CldC → CIdCMP → CIdUMP → CIdUTP → DNA. All the enzymes of this pathway are elevated in many human malignant tumors and in HEp-2 cells. In X irradiation studies with HEp-2 cells, limited to 1 or 2 radiation doses, we have obtained 3.0 to 3.8 apparent dose enhancement ratios (these represent upper limits) when cells are preincubated with inhibitors of pyrimidine biosynthesis: N-(Phosphonacetyl)-L-aspartate (PALA) and 5-fluorodeoxyuridine (FdU) or 5-fluorodeoxycytidine (FdC) + H4U Optimum conditions for radiosensitization are: PALA (0.1 mg/ml) 18-20 hr prior to FdU (0.1 μM or FdC (0.02 μM + H4U (0.1 mM) followed 6 hr later by CIdC (0.1-0.2 mM) + H4U (0.1 mM) for 56-68 hr. Viabilities of 10 ± 4% to 15 ±t 1% (±S.E.) were obtained for drug-treated unirradiated cells. Enzymatic studies indicate that this toxicity may be tumor selective. CIdC + H4 alone (at these concentrations) results in 20% substitution of CIdU for thymidine in DNA (determined by HPLC analysis). Preliminary toxicity studies indicate that mice will tolerate treatment protocols involving a single dose of PALA (200 mg/kg) followed by a dose of FdU (50 mg/kg) and 3 cycles of CldC (500 mg/kg) + H4U (100 mg/kg) at 10 hour intervals, with marginal weight loss (496). In this approach we seek to obtain preferential conversion of CIdC to CIdUTP at the tumor site by taking advantage of quantitative differences in enzyme levels between tumors and normal tissues.

AB - Our approach to overcome the problem of rapid catabolism and general toxicity encountered with 5-halogenated analogues of deoxyuridine (5-bromo, chloro or iododeoxyuridine~ which has limited their use as tumor radiosensitizers, is to utilize 5-chlorodeoxycytidine (CldC with tetrahydrouridine (H4U) We propose that CIdC, co-administered with H4 is metabolized in the following manner: CldC → CIdCMP → CIdUMP → CIdUTP → DNA. All the enzymes of this pathway are elevated in many human malignant tumors and in HEp-2 cells. In X irradiation studies with HEp-2 cells, limited to 1 or 2 radiation doses, we have obtained 3.0 to 3.8 apparent dose enhancement ratios (these represent upper limits) when cells are preincubated with inhibitors of pyrimidine biosynthesis: N-(Phosphonacetyl)-L-aspartate (PALA) and 5-fluorodeoxyuridine (FdU) or 5-fluorodeoxycytidine (FdC) + H4U Optimum conditions for radiosensitization are: PALA (0.1 mg/ml) 18-20 hr prior to FdU (0.1 μM or FdC (0.02 μM + H4U (0.1 mM) followed 6 hr later by CIdC (0.1-0.2 mM) + H4U (0.1 mM) for 56-68 hr. Viabilities of 10 ± 4% to 15 ±t 1% (±S.E.) were obtained for drug-treated unirradiated cells. Enzymatic studies indicate that this toxicity may be tumor selective. CIdC + H4 alone (at these concentrations) results in 20% substitution of CIdU for thymidine in DNA (determined by HPLC analysis). Preliminary toxicity studies indicate that mice will tolerate treatment protocols involving a single dose of PALA (200 mg/kg) followed by a dose of FdU (50 mg/kg) and 3 cycles of CldC (500 mg/kg) + H4U (100 mg/kg) at 10 hour intervals, with marginal weight loss (496). In this approach we seek to obtain preferential conversion of CIdC to CIdUTP at the tumor site by taking advantage of quantitative differences in enzyme levels between tumors and normal tissues.

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KW - Deoxycytidylate deaminase (dCMPD)

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