tetrahydrouridine has been researched along with Breast-Neoplasms* in 6 studies
1 trial(s) available for tetrahydrouridine and Breast-Neoplasms
5 other study(ies) available for tetrahydrouridine and Breast-Neoplasms
| Article | Year |
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Upregulation of cytidine deaminase in NAT1 knockout breast cancer cells.
Arylamine N-acetyltransferase 1 (NAT1), a phase II metabolic enzyme, is frequently upregulated in breast cancer. Inhibition or depletion of NAT1 leads to growth retardation in breast cancer cells in vitro and in vivo. A previous metabolomics study of MDA-MB-231 breast cancer cells suggests that NAT1 deletion leads to a defect in de novo pyrimidine biosynthesis. In the present study, we observed that NAT1 deletion results in upregulation of cytidine deaminase (CDA), which is involved in the pyrimidine salvage pathway, in multiple breast cancer cell lines (MDA-MB-231, MCF-7 and ZR-75-1). We hypothesized that NAT1 KO MDA-MB-231 cells show differential sensitivity to drugs that either inhibit cellular pyrimidine homeostasis or are metabolized by CDA.. The cells were treated with (1) inhibitors of dihydroorotate dehydrogenase or CDA (e.g., teriflunomide and tetrahydrouridine); (2) pyrimidine/nucleoside analogs (e.g., gemcitabine and 5-azacytidine); and (3) naturally occurring, modified cytidines (e.g., 5-formyl-2'-deoxycytidine; 5fdC).. Although NAT1 KO cells failed to show differential sensitivity to nucleoside analogs that are metabolized by CDA, they were markedly more sensitive to 5fdC which induces DNA damage in the presence of high CDA activity. Co-treatment with 5fdC and a CDA inhibitor, tetrahydrouridine, abrogated the increase in 5fdC cytotoxicity in NAT1 KO cells, suggesting that the increased sensitivity of NAT1 KO cells to 5fdC is dependent on their increased CDA activity.. The present findings suggest a novel therapeutic strategy to treat breast cancer with elevated NAT1 expression. For instance, NAT1 inhibition may be combined with cytotoxic nucleosides (e.g., 5fdC) for breast cancer treatment. Topics: Arylamine N-Acetyltransferase; Breast Neoplasms; Cytidine Deaminase; Female; Humans; Pyrimidines; Tetrahydrouridine; Up-Regulation | 2023 |
Nucleoside-catabolizing enzymes in mycoplasma-infected tumor cell cultures compromise the cytostatic activity of the anticancer drug gemcitabine.
The intracellular metabolism and cytostatic activity of the anticancer drug gemcitabine (2',2'-difluoro-2'-deoxycytidine; dFdC) was severely compromised in Mycoplasma hyorhinis-infected tumor cell cultures. Pronounced deamination of dFdC to its less cytostatic metabolite 2',2'-difluoro-2'-deoxyuridine was observed, both in cell extracts and spent culture medium (i.e. tumor cell-free but mycoplasma-containing) of mycoplasma-infected tumor cells. This indicates that the decreased antiproliferative activity of dFdC in such cells is attributed to a mycoplasma cytidine deaminase causing rapid drug catabolism. Indeed, the cytostatic activity of gemcitabine could be restored by the co-administration of tetrahydrouridine (a potent cytidine deaminase inhibitor). Additionally, mycoplasma-derived pyrimidine nucleoside phosphorylase (PyNP) activity indirectly potentiated deamination of dFdC: the natural pyrimidine nucleosides uridine, 2'-deoxyuridine and thymidine inhibited mycoplasma-associated dFdC deamination but were efficiently catabolized (removed) by mycoplasma PyNP. The markedly lower anabolism and related cytostatic activity of dFdC in mycoplasma-infected tumor cells was therefore also (partially) restored by a specific TP/PyNP inhibitor (TPI), or by exogenous thymidine. Consequently, no effect on the cytostatic activity of dFdC was observed in tumor cell cultures infected with a PyNP-deficient Mycoplasma pneumoniae strain. Because it has been reported that some commensal mycoplasma species (including M. hyorhinis) preferentially colonize tumor tissue in cancer patients, our findings suggest that the presence of mycoplasmas in the tumor microenvironment could be a limiting factor for the anticancer efficiency of dFdC-based chemotherapy. Accordingly, a significantly decreased antitumor effect of dFdC was observed in mice bearing M. hyorhinis-infected murine mammary FM3A tumors compared with uninfected tumors. Topics: Animals; Antimetabolites, Antineoplastic; Bacterial Proteins; Breast Neoplasms; Cell Line, Tumor; Deoxycytidine; Female; Gemcitabine; Humans; Mammary Neoplasms, Experimental; Mice; Mycoplasma hyorhinis; Mycoplasma Infections; Pyrimidine Phosphorylases; Tetrahydrouridine; Thymidine; Tumor Microenvironment | 2014 |
Five-chlorodeoxycytidine, a tumor-selective enzyme-driven radiosensitizer, effectively controls five advanced human tumors in nude mice.
The study's goals were as follows: (1) to extend our past findings with rodent tumors to human tumors in nude mice, (2) to determine if the drug protocol could be simplified so that only CldC and one modulator, tetrahydrouridine (H4U), would be sufficient to obtain efficacy, (3) to determine the levels of deoxycytidine kinase and dCMP deaminase in human tumors, compared to adjacent normal tissue, and (4) to determine the effect of CldC on normal tissue radiation damage to the cervical spinal cord of nude mice.. The five human tumors used were as follows: prostate tumors, PC-3 and H-1579; glioblastoma, SF-295; breast tumor, GI-101; and lung tumor, H-165. The duration of treatment was 3-5 weeks, with drugs administered on Days 1-4 and radiation on Days 3-5 of each week. The biomodulators of CldC were N-(Phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartyl transcarbamoylase, 5-fluorodeoxycytidine (FdC), resulting in tumor-directed inhibition of thymidylate synthetase, and H4U, an inhibitor of cytidine deaminase. The total dose of focused irradiation of the tumors was usually 45 Gy in 12 fractions.. Marked radiosensitization was obtained with CldC and the three modulators. The average days in tumor regrowth delay for X-ray compared to drugs plus X-ray, respectively, were: PC-3 prostate, 42-97; H-1579 prostate, 29-115; glioblastoma, 5-51; breast, 50-80; lung, 32-123. Comparative studies with PC-3 and H-1579 using CldC coadministered with H4U, showed that both PALA and FdC are dispensable, and the protocol can be simplified with equal and possibly heightened efficacy. For example, PC-3 with X-ray and (1) no drugs, (2) CldC plus the three modulators, (3) a high dose of CldC, and (4) escalating doses of CldC resulted in 0/10, 3/9, 5/10, and 6/9 cures, respectively. The tumor regrowth delay data followed a similar pattern. After treating mice only 11/2 weeks with CldC + H4U, 92% of the PC-3 tumor cells were found to possess CldU in their DNA. The great majority of head-and-neck tumors from patient material had markedly higher levels of dC kinase and dCMP deaminase than found in adjacent normal tissue. Physiologic and histologic studies showed that CldC + H4U combined with X-ray, focused on the cervical spinal cord, did not result in damage to that tissue.. 5-CldC coadministered with only H4U is an effective radiosensitizer of human tumors. Ninety-two percent of PC-3 tumor cells have been shown to take up ClUra derived from CldC in their DNA after only 11/2 weeks and 2 weeks of bolus i.p. injections. Enzymatic alterations that make tumors successful have been exploited for a therapeutic advantage. The great electronegativity, coupled with the relatively small Van der Waal radius of the Cl atom, may result in CldC's possessing the dual advantageous properties of FdC on one hand and BrdU and IdU on the other hand. These advantages include autoenhancing the incorporation of CldUTP into DNA by not only overrunning but also inhibiting the formation of competing TTP pools in tumors. A clinical trial is about to begin, with head-and-neck tumors as a first target of CldC radiosensitization. Topics: Animals; Breast Neoplasms; Carcinoma, Squamous Cell; Combined Modality Therapy; DCMP Deaminase; Deoxycytidine; Deoxycytidine Kinase; Female; Glioblastoma; Humans; Lung Neoplasms; Male; Mice; Mice, Nude; Neoplasm Proteins; Neoplasms; Prostatic Neoplasms; Radiation-Sensitizing Agents; Radiotherapy Dosage; Spinal Cord; Tetrahydrouridine | 2001 |
5-Iododeoxyuridine increases the efficacy of the radioimmunotherapy of human tumors growing in nude mice.
Recently, there has been much interest in the use of radionuclide conjugated monoclonal antibodies for the treatment of human malignancies. One way to potentially maximize the therapeutic effectiveness of radioimmunotherapy would be to sensitize tumor cells to the radiation dose delivered by the antibody. Since radioimmunotherapy can potentially treat disseminated disease, including micrometastasis, we chose to study a halogenated pyrimidine radiosensitizer, a class of compounds that affect nonhypoxic cells. 5-Iododeoxyuridine, administered with pyrimidine metabolism modulators, increased the therapeutic effectiveness of radioimmunotherapy, resulting in individual cures of human tumors growing in BALB/c nu/nu (nude) mice. 5-Iododeoxyuridine was administered with N-(phosphonacetyl)-L-aspartic acid and 5-fluoro-deoxycytidine plus tetrahydrouridine. This drug treatment was combined with radioimmunotherapy using 131I conjugated to a monoclonal antibody, Mc5. Mc5 binds to a mucin component of the human milk fat globule. This antigen is expressed on the surface of MX-1 cells, the transplantable human tumor used in this study. Tumor-bearing mice treated with both the drug protocol and 131I-Mc5 (540 microCi, 10 microCi/micrograms) showed a regression in average tumor volume. The average tumor volume was reduced below the initial size at treatment for 50 days; two of five cures were obtained. Neither cures nor regressions were observed with either the drug or antibody treatments alone. Our results indicate the potential for increasing the therapeutic effectiveness of radioimmunotherapy of human solid tumors with halogenated pyrimidines. Topics: Animals; Aspartic Acid; Breast Neoplasms; Deoxycytidine; Drug Therapy, Combination; Humans; Idoxuridine; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Phosphonoacetic Acid; Radiation-Sensitizing Agents; Radioimmunotherapy; Tetrahydrouridine; Transplantation, Heterologous | 1992 |
Incorporation of 5-fluorodeoxycytidine and metabolites into nucleic acids of human MCF-7 breast carcinoma cells.
Several mechanisms of action have been proposed for the antitumor agents, 5-fluorouracil (FUra) and 5-fluorodeoxyuridine (FdUrd), including their incorporation into both cellular RNA and DNA. Another fluorinated pyrimidine, 5-fluorodeoxycytidine (FdCyd), has been shown to be even more active than FdUrd against certain experimental tumors. Although FdCyd is deaminated to FdUrd, the precise mechanism of action of this agent has remained unclear. We have therefore monitored the incorporation of FdCyd and its metabolites into the nucleic acids of human MCF-7 breast carcinoma cells. The results demonstrate the internucleotide incorporation of FdCyd in MCF-7 DNA. The results also demonstrate that FUra residues are detectable in both MCF-7 DNA and RNA following treatment with FdCyd. Cytidine and deoxycytidylate deaminase inhibitors increased the extent of (FdCyd) DNA synthesis, but they had little if any effect on formation of (FUra) RNA. In contrast, deoxyuridine increased incorporation of FdCyd into DNA and blocked the formation of FUra RNA. Deoxyuridine also enhanced the cytotoxicity associated with FdCyd treatment. The present results further demonstrate that FdCyd inhibits postsynthetic methylation of MCF-7 DNA. These findings would suggest that FdCyd has multiple mechanisms of action and that incorporation of this agent into DNA distinguishes its effects from those of FUra and FdUrd. Topics: Azacitidine; Breast Neoplasms; Cell Line; Cell Survival; Decitabine; Deoxycytidine; Deoxyuridine; DNA, Neoplasm; Floxuridine; Humans; Methylation; RNA, Neoplasm; Tetrahydrouridine | 1986 |