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Inhibition of Cyclophosphamide and Mitomycin C-Induced Sister Chromatid Exchanges in Mice by Vitamin C

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Inhibition of Cyclophosphamide and Mitomycin C-Induced Sister Chromatid Exchanges in Mice by Vitamin C ICANCERRESEARCH46,2670-2674, June 19861 Inhibition of Cyclophosphamide and Mitomycin C-induced Sister Chromatid Exchanges in Mice by Vitamin C G. Krishna,' J. Nath, and T. Ong Natio,wilnstitutefor OccupationaiSafety and Health, Division ofRespiratory Disease Studies, Morgansown, West Virginia 26505-2888 fG. K., T. 0.], andDivision of PlantandSoil Sciences,West VirginiaUniversity,Morgantown,West Visijnia 265O6fJ.N.J ABSTRACF The research reported here was performed to determine the effect of ascorbic acid on SCEs induced by CPA and MMC in Ascorbic acid (vitamin C) is known to act as an antimutagen and in vivo and in vivo/in vitro conditions in bone marrow and anticarcinogen in several test systems. However, there is no report of its spleen cells of mice. Analysis of SCEs is a sensitive cytogenetic effect on carcinogen-induced chromosomal damage in vii'o in animals. technique for detecting cellular chromosomal damage (11). The present study was performed to determine whether or not ascorbic SCEs are visualized as reciprocal exchangesof staining inten acid affects sister ébromatidexchanges (SCEs) induced by cyclophos sities between sister chromatid arms in metaphase cells that phamide (CPA) and mitomycin C (MMC) in bone marrow and spleen cells in mice. The results indicate that ascorbic acid per se did not cause have replicated twice in the presenceof BrdUrd. a significantincreaseinSCEsin mice.However,increasingconcentra tions of ascorbic acid caused decreasing levels of CPA- and MMC induced SCEs in both cell types in rho. At the highest concentration of MATERIALS AND METHODS ascorbic acid, 6.68 gfkg, approximately 75 and 40% SCE inhibition in Animals. Male CD-I mice were purchased from Charles River Breed both cell types was noted for CPA and MMC, respectively. likewise, under in ris'o/in ritro conditions (exposure of *nimals to experimental ing Laboratories, Wilmington, MA. All animals were 2-3 mo old and chemicals followed by culturing of cells), ascorbic acid caused a dose weighed 25—30g.Mice were housed separately in groups of 4 in cages related decrease in CPA- and MMC-induced SCEs, up to a dose of 3.34 containing hardwood chip bedding and excelsior nesting material. g/kg. At this concentration, approximately 50% CPA- and MMC-induced Water and Purina laboratory rodent chow were provided ad libitum SCE inhibition was observed in both cell types studied. Thus, ascorbic throughout the period of animal holding and experimentation. acid acts as an anti-SCE agent in both in rivo and in rho/in ritro Drug Treatment. CPA and MMC (Sigma Chemical Co., St. Louis, conditions in mice. MO) were dissolved in PBS and immediately injected i.p. in a volume equivalent to 10 ml/kg of body weight (40 mg of CPA and 2.5 mg of MMC per kg of body weight). These concentrations were chosen INTRODUCI1ON because they caused a significant increase in SCE levels in mice in earlier studies (12—14).L-AscorbiCacid sodium salt (Calbiochem-Behr Ascorbic acid (vitamin C) is known to act as an antimutagen ing Corp., La Jolla, CA), was dissolved in sterile distilled water and and anticarcinogen in various test systems (1). Under in vitro injected (i.p.) in different dosages (1.67, 3.34, and 6.68 g/kg of body conditions, it decreasescarcinogen-induced gene mutations (2, weight) immediately after drug treatment. These ascorbic acid concen 3), SCEs2 (4), and chromosomal breakages (5, 6). In humans, trations were chosen based on our preliminary studies and the studies ascorbic acid prophylaxis has been reported to decreasechro reported by others (15). Negative control animals received an equivalent volume of PBS. For the ascorbic acid control, only the highest dose mosomal damagein peripheral lymphocytes ofcoal-tar workers (6.68 g/kg of body weight) was used. occupationallyexposed to polycyclic aromatic hydrocarbons In Vi,'o Sister Chromatid Exchange Assay. Paraffin-coated BrdUrd and benzene (7). It has been shown to be anticarcinogenic in tablets(50 mg;BoehringerMannheinBiochemicals,Indianapolis,IN) rodents treated with UV radiation, benzo(a)pyrene,and nitroso were inserted under the skin on the flank (16). At 16 h after BrdUrd compounds(8). In terminal humancancerpatients,supplemen implantation,experimentalchemicalswereinjected.Fiveh afterchem tal ascorbateis known to prolongsurvivaltimes (9). A signifi ical treatment, animals were given injections of colchicine (4 mg/kg cant dose-related decrease in the appearance of spontaneous GIBCO) and were sacrificed by cervical dislocation 3 h later. For bone mammary tumors following dietary ascorbicacid in 11111mice marrow preparations, both femora and tibia were isolated, and the has been reported (10). adherent muscle was removed. Each bone was cleaned with 70% ethyl To date, there is no report of the in vivoanticlastogenicity alcohol, and the head was cut offwith scissors. The marrow was flushed studies of ascorbic acid in animals. Likewise there is a relative out with physiological saline into a centrifuge tube, followed by cen paucity of data on metabolicactivation, detoxification, trans trifugation at 285 x g for 6 mm. The supernatant was removed, and portation, and distribution of test compoundsin the intact the pellet was resuspended with hypotonic (0.075 M KC1)solution for animal. Also, cytogenetic studies in humans would involve 20 mm at 37'C and recentrifuged. The cells were fixed in 2 changes of fixative, 10 mm each, in methanol:acetic acid (3:1). The cells were collection of peripheral lymphocytes and/or bone marrow and resuspended in approximately 0.5 ml of fixative and dropped onto culturing such cells for 1—2cellcyclesto assessclastogenic/ precleaned, chilled wet slides and air dried for 24 h. anticlastogenic effects of agents to which humans are exposed. For spleencellpreparations,spleensfromthesameanimalsusedfor However, the resultsfrom suchin vivo/in vitromonitoringmay bone marrow removal were removed by opening the abdominal cavity. not be comparable to the in vivo situations. Thus, to better The spleens were transferred into 15-ml centrifuge tubes, each contain assessthe effect of vitamin C, the genotoxicity studies in both ing 2 ml of Hanks' balanced salt solution (GIBCO). Spleens were in vivo/in vitro and in vivo situations in animals should prove mashed with a spatula, and the debris was removed. Cells were treated valuable. with hypotonic solution and fixed, and slides were prepared for SCE analysis as described for bone marrow cells. Received11/19/85; revised 1/15/86; accepted2/24/86. In Vipo/in Vitro Sister Chromatid Exchange Assay. Animals were The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in given injections of experimental chemicals and sacrificed 8 h later by accordance with 18 U.S.C. Section 1734 solely to indicate this fact. cervical dislocation. In these experiments, animals were not implanted 1 To whom requests for reprints should be addressed. with BrdUrd tablets. Bone marrow cells were obtained as described in 2 The abbreviations used are: SCEs, sister chromatid exchanges; CPA, cyclo the previous section except that bone marrow was flushed out with phosphamide; MMC, mitomycin C; BrdUrd, 5-bromo-2'-deoxyuridine;PBS, phosphate-bufferedsaline; GIBCO, Grand Island BiologicalCo., Grand Island, Ham's F-12 medium (Flow Laboratories, McLean, VA) into a 15-mi NY; RI, replicativeindex. centrifuge tube. After centrifugation, bone marrow cells (approximately 2670 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1986 American Association for Cancer Research. VITAMIN C AND CARCINOGEN-INDUCED SCES IN MICE 1.5 x 10@cells) were cultured as described in an earlier study (17). At tested in both bone marrow and spleen cells in vivo. At the 30 h after incubation, colchicine (33 @iMfinalconcentration) was added, highest concentration, 6.68 g/kg, it causedapproximately 75% and cells were harvested 3 h later. SCE inhibition in both cell types. Spleens were obtained aseptically by opening the abdominal cavity Similar in vivo data following exposure ofanimals to ascorbic of the same mice used for bone marrow isolation. They were then acid and MMC are shown in Table 2. MMC (2.5 mg/kg) also processed and cultured as described by Neft et a!. (18) with modifica induced about a 7-fold increase in SCEs. Ascorbic acid, as in tion. The cell suspension (approximately 1.5 x 10@cells) was cultured in 5 ml of medium consisting of: 3.70 ml of RPM! 1640 with L CPA experiments, caused a dose-related decrease in MMC glutamine and 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid induced SCEs. At the highest concentration (6.68 g/kg), it buffer (GIBCO); 1 ml of heat-inactivated fetal bovine serum (GIBCO); causedapproximately a 40% decreasein SCE level in both cell 0.05 ml of penicillin and streptomycin (Flow Laboratories); 0.05 ml of types. These differences were statistically significant (P < 0.01). 200 m@iL-glutaminesolution (GIBCO); 1 x l0@ M2-mercaptoethanol The results of the inhibitory effect of ascorbic acid on CPA (Sigma); 20 gzMBrdUrd (Sigma); and 0.2 ml of lipopolysaccharide and MMC-induced SCEs, in in vivo/in vitro conditions, are (Escherichia coli serotype 01l1:B4; Sigma stock of600 zg/ml in PBS). presented in Tables 3 and 4, respectively. Ascorbic acid caused The cell suspension with the complete medium was dispensed into 25- a dose-related decreasein SCEs induced by both drugs in both cm2 Falcon tissue culture flasks, covered with aluminum foil, and then cell types up to a concentration of 3.34 g/kg. At this concentra incubated at 37'C with 98% relative humidity. At 40 h after incubation, colchicine (33 @iMfinalconcentration) was added, and cells were har tion, it caused 61 and 41% CPA-induced SCE inhibition in vested 3 h later. bone marrow and spleen cells, respectively. Under the same in Harvesting, Staining, and Scoring. For harvesting cultures, the con vivo/in vitro conditions, ascorbic acid (3.34 g/kg) caused51and tents of the flask were decanted into 15-mI Falcon centrifuge tubes.
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