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Cancer Research Sep 1997Antitumor and radiosensitizing effects of (E)-2'-deoxy-2'-(fluromethylene) cytidine (FMdC), a novel inhibitor of ribonucleotide reductase, were evaluated on nude mice...
Antitumor and radiosensitizing effects of (E)-2'-deoxy-2'-(fluoromethylene) cytidine, a novel inhibitor of ribonucleoside diphosphate reductase, on human colon carcinoma xenografts in nude mice.
Antitumor and radiosensitizing effects of (E)-2'-deoxy-2'-(fluromethylene) cytidine (FMdC), a novel inhibitor of ribonucleotide reductase, were evaluated on nude mice bearing s.c. xenografts and liver metastases of a human colon carcinoma. FMdC given once daily or twice weekly has a dose-dependent antitumor effect. The maximum tolerated dose in the mice was reached with 10 mg/kg applied daily over 12 days. Twice weekly administration of FMdC reduced its toxicity but lowered the antitumor effect. Treatment of preestablished liver micrometastases obtained via intrasplenic injection of tumor cells, with 5 or 10 mg/kg FMdC, significantly prolonged the survival of the mice as compared to controls (P < 0.025 and P < 0.001, respectively). Ten mg/kg resulted in longer survival than 5 mg/kg FMdC (P < 0.05). Radiotherapy alone of s.c. xenografts (10 fractions over 12 days) yielded the radiation dose required to produce local tumor control in 50% of the treated mice (TCD50) of 43.0 Gy. When combined with FMdC, TCD50 was reduced to 22.5 and 19.0 Gy at doses of 5 and 10 mg/kg given i.p. 1 h before each irradiation, respectively. The corresponding enhancement ratios were 1.91 and 2.43, respectively. FMdC produced moderate and reversible myelosuppression. When 5 mg/kg FMdC was combined with irradiation, there was no increased skin or hematological toxicity as compared to radiotherapy or FMdC alone. At the 10 mg/kg level, however, lower leukocyte counts were observed. These results show that FMdC appears to be a potent anticancer drug and radiosensitizer.
Topics: Animals; Antineoplastic Agents; Carcinoma; Colonic Neoplasms; Deoxycytidine; Humans; Injections, Intraperitoneal; Injections, Intravenous; Leukocyte Count; Liver Neoplasms; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Radiation-Sensitizing Agents; Ribonucleotide Reductases; Survival Analysis; Transplantation, Heterologous
PubMed: 9307288
DOI: No ID Found -
Acta Biochimica Polonica 2000(E)-2'-deoxy-2'-(fluoromethylene)-cytidine (FMdC), a deoxycytidine analog displaying a very high toxicity toward a variety of solid tumor cell lines and xenografts, is...
(E)-2'-deoxy-2'-(fluoromethylene)-cytidine (FMdC), a deoxycytidine analog displaying a very high toxicity toward a variety of solid tumor cell lines and xenografts, is activated intracellularly by deoxycytidine kinase (dCK). We have compared cytotoxicity of FMdC towards a human promyeolocytic leukemia line HL-60 and a human colorectal carcinoma line COLO-205. Despite dCK activity being by far the highest in cells of lymphoid origin, the effects of FMdC were detectable at the lowest drug concentration only in a solid tumor cell line, and at higher concentrations they were qualitatively similar in the two tumor lines (increased cell protein content, cell cycle block and apoptosis). Apparently, low dCK activity in solid tumor cells sufficiently activates FMdC to yield cytotoxic effects, while high dCK activity in leukemia cells does not increase its cytotoxicity.
Topics: Antineoplastic Agents; Colorectal Neoplasms; Deoxycytidine; Drug Screening Assays, Antitumor; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Tumor Cells, Cultured
PubMed: 10961690
DOI: No ID Found -
NMR in Biomedicine Apr 2003(E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC), was evaluated as a potential treatment for malignant gliomas using the rat 9L brain tumor model. FMdC was shown to be...
(E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC), was evaluated as a potential treatment for malignant gliomas using the rat 9L brain tumor model. FMdC was shown to be an effective inhibitor of cell proliferation in cultured 9L cells with an EC(50) of 40 ng/ml. In vitro studies also revealed that this compound significantly inhibited incorporation of [(3)H]thymidine in 9L cells. In vivo therapeutic efficacy of FMdC was evaluated in rats harboring intracerebral 9L tumors which were treated daily with 15 mg/kg, i.p. Treatment response was quantified from changes in tumor growth rates as assessed from sequential magnetic resonance imaging (MRI) tumor volume measurements. In vivo tumor cell kill in individual animals was calculated by fitting tumor volume data with an iterative computer routine. It was estimated that therapeutically responsive rats treated with FMdC daily produced a >/= 0.1 log kill per therapeutic dose which resulted in a significant reduction in tumor growth rate. In addition, localized (1)H-MRS of intracerebral 9L tumors revealed changes in metabolite levels which correlated with therapeutic response. These results provide evidence supporting the use of FMdC in clinical trials for the treatment of malignant gliomas and reveals that MR can play an important role in the pre-clinical evaluation of novel compounds using orthotopic tumor models.
Topics: Animals; Antineoplastic Agents; Apoptosis; Brain Neoplasms; Cell Division; Cell Line, Tumor; Cell Survival; Deoxycytidine; Dose-Response Relationship, Drug; Feasibility Studies; Glioma; Imaging, Three-Dimensional; Injections, Intraperitoneal; Magnetic Resonance Imaging; Male; Neoplasm Transplantation; Protons; Rats; Rats, Inbred F344; Thymidine; Treatment Outcome
PubMed: 12730947
DOI: 10.1002/nbm.813 -
British Journal of Cancer Aug 1998The precise mechanism of fever and flu-like syndrome that occurs in treatment with deoxycytidine analogues remains unclear. This study demonstrated a strong correlation... (Clinical Trial)
Clinical Trial
The precise mechanism of fever and flu-like syndrome that occurs in treatment with deoxycytidine analogues remains unclear. This study demonstrated a strong correlation between plasma interleukin 6 levels and fever in treatment with oral (E)-2'-deoxy-2'(fluoromethylene)cytidine, another deoxycytidine analogue.
Topics: Administration, Oral; Antineoplastic Agents; Deoxycytidine; Fever; Humans; Interleukin-6
PubMed: 9703288
DOI: 10.1038/bjc.1998.504