The metabolism of 5-fluorocytosine-214C and of cytosine-14C in the rat and the disposition of 5-fluorocytosine-214C in man

Koechlin, Bernard A.; Rubio, F.; Palmer, S H; Gabriel, Thomas F.; Duschinsky, Robert

doi:10.1016/0006-2952(66)90254-1

Cited by 120 publications

(41 citation statements)

References 7 publications

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“…The results of our studies confirm this observation and quite convincingly demonstrate the profound effect which renal function has on serum concentrations of 5-FC. These results are in keeping with expectations, since 85 to 95 % of an oral dose of 5-FC is excreted unchanged in the urine of humans (7).…”

Section: 96supporting

confidence: 92%

Pharmacological Studies with 5-Fluorocytosine

Block

Bennett

1972

Antimicrob Agents Chemother

108

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A cylinder plate bioassay for 5-fluorocytosine (5-FC) is described which permits determination of 5-FC concentrations in biological fluids in the presence of amphotericin B. Using this assay, we determined serum concentrations in 12 patients after a single dose of drug and in 8 patients receiving daily 5-FC at 6-hr intervals (4 to 120 days). Drug was detectable in serum as early as 0.5 hr and concentrations were measurable as long as 24 hr after a dose, regardless of renal function. Peak concentrations occurred 6 hr after the initial drug dose, but were seen between 1 and 2 hr after a dose in all patients receiving a minimum of 4 days of therapy. Mild to moderate renal impairment produced marked increases in peak 5-FC concentrations in the serum of a group of eight patients on three different dosage schedules. Five patients were studied before and after amphotericin B-induced renal insufficiency. Peak concentrations increased from 14 to 142% concomitant with the change in renal function. Parallel studies in rabbits confirmed the results in our patients. 5-FC half-life in the serum of 10 rabbits increased from 3.35 0.27 to 24.63 0.70 hr after experimentally induced acute renal failure. Concentrations of 5-FC in the cerebrospinal fluid of five patients ranged from 17 to 62 ,ug/ml and were 74.4 + 5.6% of simultaneously determined serum concentrations. The effect of renal function on 5-FC concentrations in cerebrospinal fluid was similar to that seen with serum.

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Section: 96supporting

confidence: 92%

Pharmacological Studies with 5-Fluorocytosine

Block

Bennett

1972

Antimicrob Agents Chemother

108

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“…Currently, one of the most efficient and extensively studied prodrug activation systems is the bacterial cytosine deaminase (CDase) in combination with 5-fluorocytosine (5-FC). [1][2][3][4][5][6][7] CDase, an enzyme present in fungi and bacteria 8,9 but absent in mammalian cells, 10 deaminates the nontoxic prodrug 5-FC to its highly toxic derivative 5-fluorouracil (5-FU).…”

Section: Introductionmentioning

confidence: 99%

Modified vaccinia virus Ankara as a vector for suicide gene therapy

et al. 2007

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Modified vaccinia virus Ankara (MVA) has been used successfully to express various antigens for the development of vaccines. Here we show that MVA can also be used as an efficient vector for the transfer of suicide genes to cancer cells. We have generated a new and highly potent suicide gene, FCU1, which encodes a fusion protein derived from the yeast cytosine deaminase and uracil phosphoribosyltransferase genes. We now describe the therapeutic benefit of using MVA to deliver and express the FCU1 gene in cancer cells. MVA-mediated transfer of the FCU1 gene to various human tumor cells results in the production of a bifunctional intracellular enzyme, such that exposure to the prodrug 5-FC suppresses the growth of the tumor cells both in vitro and in vivo. Moreover, we report a more potent tumor growth delay at lower doses of 5-FC using MVA-FCU1 in comparison to adenovirus encoding FCU1. Prolonged therapeutic levels of cytotoxic 5-FU were detected in tumors in mice treated with both MVA-FCU1 and 5-FC while no detectable 5-FU was found in the circulation. This original combination between MVA and FCU1 represents a potentially safe and attractive therapeutic option to test in man.

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“…2 and 15; see also an independent report of Danielsen et al (16)] and have demonstrated significant in vivo antitumor effects on human colorectal tumor xenografts transduced with CD when the host animal is treated with the prodrug 5-fluorocytosine (5FCyt) (2,3). CD was chosen because 5FCyt is very nontoxic in man (17,18); the toxic anabolite 5-fluorouracil (5FUra) is the drug of choice for colorectal carcinoma (19)(20)(21); and 5FUra can readily diffuse into and out of cells by nonfacilitated diffusion (22). We have hypothesized that to produce a significant therapeutic benefit, the required efficiency of CD gene transfer into a tumor mass may be quite small, since tumor cells which selectively express CD may produce significant amounts of5FUra which can readily diffuse into and kill neighboring untransduced tumor cells.…”

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confidence: 99%

Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase.

Huber

Austin

Richards

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

379

245

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The gene encoding cytosine deaminase (CD) has been expressed in the human colorectal carcinoma cell line WiDr. Metabolism studies confirm that tumor cells expressing CD convert the very nontoxic prodrug 5-fluorocytosine (5FCyt) to 5-fluorouracil (5FUra) and 5FUra metabolites. Tumor xenografts composed of CD-expressing cells can selectively generate tumor levels of >400 iAM 5FUra when the host mouse is dosed with nontoxic levels of 5FCyt. The selective metabolic conversion of 5FCyt to 5FUra in CD-expressing tumor cells results in the inhibition of thymidylate synthase and incorporation of 5FUra into RNA. 5FUra is also liberated into the surrounding environment when CD-expressing tumor cells are treated with 5FCyt. The liberated 5FUra is able to kill neighboring, non-CD-expressing tumor cells in vitro and in vivo.Most importantly, when only 2% of the tumor mass contains CD-expressing cells (98% non-CD-expressing cells), significant regresions in all tumors are observed when the host mouse is dosed with nontoxic levels of 5FCyt.We have previously reported our efforts to develop a therapeutic approach using gene transfer technology for the treatment of primary and metastatic tumors (1-4). This approach, virus-directed enzyme/prodrug therapy, exploits transcriptional differences between normal and neoplastic cells to selectively kill cancer cells. An artificial chimeric gene is created that is composed of tissue-specific transcriptional regulatory sequences linked to the coding domain of a nonmammalian enzyme. The nonmammalian enzyme can metabolically activate a nontoxic prodrug to a cytotoxic anabolite. Ifthe tissue-specific regulatory sequences are from a tumor-associated marker gene such as the carcinoembryonic antigen gene (5, 6), the prostate-specific antigen gene (7,8), or the a-fetoprotein gene (9, 10), then the artificial chimeric gene will result in tumor-specific expression of the nonmammalian enzyme and, consequently, in tumor-specific production of the cytotoxic metabolite.A critical issue influencing the therapeutic benefit of this approach will be the efficiency of gene transfer into a solid tumor. However, the efficacy of this gene therapy approach is dependent not only on the efficiency of gene transfer but also on the enzyme/prodrug system. Various enzyme/prodrug systems have been reported (1)(2)(3)(11)(12)(13)(14). A prodrug that is metabolically converted into a toxic anabolite that is not readily diffusible from one tumor cell into another will require very high gene transfer efficiency. However, if the toxic anabolite is readily diffusible, then the efficiency of gene transfer into the tumor mass may be quite low but still be able to achieve a significant therapeutic effect. Cells were lysed by freeze-thawing and centrifuged for 10 min at 8000 x g. The conditioned medium and the cell extract supernatant were evaporated to dryness, dissolved in deionized water (1 ml for medium; 100 !A for extract). Aliquots (20 1.l) of each sample were analyzed by HPLC on a Partisphere C18 column (4.6 mm x...

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The metabolism of 5-fluorocytosine-214C and of cytosine-14C in the rat and the disposition of 5-fluorocytosine-214C in man

Cited by 120 publications

References 7 publications

Pharmacological Studies with 5-Fluorocytosine

Pharmacological Studies with 5-Fluorocytosine

Modified vaccinia virus Ankara as a vector for suicide gene therapy

Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase.

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