TY - JOUR
T1 - Marked radiosensitization of cells in culture to X ray by 5-chlorodeoxycytidine coadministered with tetrahydrouridine, and inhibitors of pyrimidine biosynthesis
AU - Perez, Liliana M.
AU - Mekras, John A.
AU - Briggle, Thomas V.
AU - Greer, Sheldon
N1 - Funding Information:
nandez in the preparation of this manuscript. This research was supported by a gift from the Women’s Cancer Association of the University of Miami and gifts from the private sector including Readmore Publications and the Weeks Endowment Fund. This paper is dedicated to the memory of Dr. Henry Kaplan who recognized the clinical potential of my discovery of the radiosensitization of cells to 5-bromouracil as evidenced by the many outstanding papers on this subject that emanated from his laboratory; this was a great source of encouragement to us. (S.G.). This paper is also dedicated to the memory of Guillermo J. Perez (father of L.P.) who died while these studies were being pursued. Accepted for publication 22 March 1984.
Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 1984/8
Y1 - 1984/8
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.
KW - 5-Chlorodeoxycytidine (CIdC)
KW - 5-Fluorodeoxycytidine (FdC)
KW - 5-Fluorodeoxyuridine (FdU)
KW - Deoxycytidine kinase (dCK)
KW - Deoxycytidylate deaminase (dCMPD)
KW - Radlosensitization
KW - Tetrahydrouridine (HU) N-(Phosphonacetyl)-L-aspartate (PALA)
KW - Tumor-directed toxicity
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U2 - 10.1016/0360-3016(84)90367-5
DO - 10.1016/0360-3016(84)90367-5
M3 - Article
C2 - 6236189
AN - SCOPUS:0021218996
VL - 10
SP - 1453
EP - 1458
JO - International Journal of Radiation Oncology Biology Physics
JF - International Journal of Radiation Oncology Biology Physics
SN - 0360-3016
IS - 8
ER -