Evaluation Of The Genotoxicity Of Euterpe Oleraceae Mart. (arecaceae) Fruit Oil (açaí), In Mammalian Cells In Vivo

E. oleracea is a tropical plant from the Amazon region, with its fruit used for food, and traditionally, as an antioxidant, anti-inflammatory, hypocholesterolemic, for atherosclerotic disease, and has anticancer properties. The oil of the fruit has antidiarrheic, anti-inflammatory and antinociceptive activities, but without genotoxicity evaluation. Therefore, the aim of this study was to evaluate the genotoxic potential of E. oleracea fruit oil (EOO), in rat cells. Male Wistar rats were treated with EOO by gavage at doses of 30, 100 and 300 mg/kg, for 14 days, within a 24 h interval. The DNA damage in the leukocytes, liver, bone marrow and testicular cells, was assessed by the comet assay, and the clastogenic/aneugenic effects in the bone marrow cells, by the micronucleus test. Our phytochemicals characterization of the EOO showed the presence of vanillic, palmitic, γ-linolenic, linoleic, oleic, cinnamic, caffeic, protocatechuic, ferulic, syringic acids, and flavonoids quercetin and kaempferol rutinoside as the main constituents. Both cytogenetic tests performed showed that EOO presented no significant genotoxic effects in the analyzed cells, at the three tested doses. These results indicate that, under our experimental conditions, E. oleracea fruit oil did not reveal genetic toxicity in rat cells. © 2016.93131

Fruit Extract Of The Medicinal Plant Crataegus Oxyacantha Exerts Genotoxic And Mutagenic Effects In Cultured Cells

Crataegus oxyacantha, a plant of the Rosaceae family also known “English hawthorn, haw, maybush, or whitethorn,” has long been used for medicinal purposes such as digestive disorders, hyperlipidemia, dyspnea, inducing diuresis, and preventing kidney stones. However, the predominant use of this plant has been to treat cardiovascular disorders. Due to a lack of studies on the genotoxicity of C. oxyacantha, this investigation was undertaken to determine whether its fruit extract exerts cytotoxic, genotoxic, or clastogenic/aneugenic effects in leukocytes and HepG2 (liver hepatocellular carcinoma) cultured human cells, or mutagenic effects in TA100 and TA98 strains of Salmonella typhimurium bacterium. Genotoxicity analysis showed that the extract produced no marked genotoxic effects at concentrations of 2.5 or 5 µg/ml in either cell type; however, at concentrations of 10 µg/ml or higher significant DNA damage was detected. The micronucleus test also demonstrated that concentrations of 10 µg/ml or higher produced clastogenic/aneugenic responses. In the Ames test, the extract induced mutagenic effects in TA98 strain of S. typhimurium with metabolic activation at all tested concentrations (2.5 to 500 µg/ml). Data indicate that, under certain experimental conditions, the fruit extract of C. oxyacantha exerts genotoxic and clastogenic/aneugenic effects in cultured human cells, and with metabolism mutagenicity occurs in bacteria cells. © 2017 Taylor & Francis8016117

In Vivo Evaluation Of The Genetic Toxicity Of Rubus Niveus Thunb. (rosaceae) Extract And Initial Screening Of Its Potential Chemoprevention Against Doxorubicin-induced Dna Damage

Ethnopharmacological relevance Rubus niveus Thunb. plant belongs to Rosaceae family and have been used traditionally to treat wounds, burns, inflammation, dysentery, diarrhea and for curing excessive bleeding during menstrual cycle. The present study was undertaken to investigate the in vivo genotoxicity of Rubus niveus aerial parts extract and its possible chemoprotection on doxorubicin (DXR)-induced DNA damage. In parallel, the main phytochemicals constituents in the extract were determined. Materials and methods The animals were exposed to the extract for 24 and 48 h, and the doses selected were 500, 1000 and 2000 mg/kg b.w. administered by gavage alone or prior to DXR (30 mg/kg b.w.) administered by intraperitoneal injection. The endpoints analyzed were DNA damage in bone marrow and peripheral blood cells assessed by the alkaline alkaline (pH>13) comet assay and bone marrow micronucleus test. Results and conclusion The results of chemical analysis of the extract showed the presence of tormentic acid, stigmasterol, quercitinglucoronide (miquelianin) and niga-ichigoside F1 as main compounds. Both cytogenetic endpoints analyzed showed that there were no statistically significant differences (p>0.05) between the negative control and the treated groups with the two higher doses of Rubus niveus extract alone, demonstrating absence of genotoxic and mutagenic effects. Aneugenic/clastogenic effect was observed only at 2000 mg/kg dose. On the other hand, in the both assays and all tested doses were observed a significant reduction of DNA damage and chromosomal aberrations in all groups co-treated with DXR and extract compared to those which received only DXR. These results indicate that Rubus niveus aerial parts extract did not revealed any genotoxic effect, but presented some aneugenic/clastogenic effect at higher dose; and suggest that it could be a potential adjuvant against development of second malignant neoplasms caused by the cancer chemotherapic DXR.1648995Alves, A.B.C., Santos, R.S., Calil, S.S., Niero, R., Lopes, J.S., Perazzo, F.F., Rosa, P.C.P., Maistro, E.L., Genotoxic assessment of Rubus imperialis (Rosaceae) extract in vivo and its potential chemoprevention against cyclophosphamide-induced DNA damage (2014) Journal of Ethnopharmacology, 153, pp. 694-700Burlinson, B., Tice, R.R., Speit, G., Agurell, E., Brendler-Schwaab, S.Y., Collins, A.R., Escobar, P., Hartmann, A., Fourth international workgroup on genotoxicity testing: Results of the in vivo comet assay workgroup (2007) Mutation Research, 627, pp. 31-35Choi, J., Lee, K.T., Ha, J., Yun, S.Y., Ko, C.D., Jung, H.J., Park, H.J., Antinociceptive and antiinflammatory effects of Niga-ichigoside F1 and 23-hydroxytormentic acid obtained from Rubus coreanus (2003) Biological Pharmaceutical Bulletin, 26, pp. 1436-1441Fedato, R.P., Maistro, E.L., Absence of genotoxic effects of the coumarin derivative 4-methylesculetin in vivo and its potential chemoprevention against doxorubicin-induced DNA damage (2014) Journal of Applied Toxicology, 34, pp. 33-39Ferguson, L.R., Antimutagens as cancer chemopreventive agents in the diet (1994) Mutation Research, 307, pp. 395-410Finn, C.E., Rubus spp., blackberry (2008) The Encyclopedia of Fruits and Nuts, pp. 348-351. , J. Janick, R.E. Paull, CABI Cambridge, MAGeorge, B.P., Parimelazhagan, T., Saravanan, S., Chandran, R., Anti-inflammatory, analgesic and antipyretic properties of Rubus niveus Thumb. Root acetone extract (2013) Pharmacologia, 4, pp. 228-235George, B.P., Parimelazhagan, T., Sajeesh, T., Saravanan, S., Antitumor and wound healing properties of Rubus niveus Thumb. Root (2014) Journal of Environmental Pathology, Toxicology and Oncology, 33, pp. 145-158Gerrish, G., Stemmermann, R.L., Gardner, D.E., The distribution of Rubus species in the State of Hawaii (1952) Cooperative Park Studies Unit Technical Report. Report No. 85, p. 33. , University of Hawaii, Manoa, HonoluluGollapudi, B.B., McFadden, L.G., Sample size for the estimation of polychromatic to normochromatic erithrocyte ratio in the bone marrow micronucleus test (1995) Mutation Research, 347, pp. 97-99Hagmar, L., Bonassi, S., Stromberg, U., Brogger, A., Knudson, J.E., Norppa, H., Reuterwall, C., Chromosomal aberration in human lymphocytes predict human cancer: A report from the European Study Group on Cytogenetic Biomarkers and Health (ESCH) (1998) Cancer Research, 58, pp. 4117-4121Hartmann, A., Speit, G., The contribution of cytotoxicity to DNA - Effects in the single cell gel test (comet assay) (1997) Toxicology Letters, 90, pp. 183-188Hartmann, A.A., Argurell, E., Beevers, C., Brendler-Schawabb, S., Burlinson, B., Clay, P., Collins, A., Tice, R.R., Recommendations for conducting the in vivo alkaline comet assay (2003) Mutagenesis, 18, pp. 45-51Kanegusuku, M., Benassi, J.C., Pedrosa, R.C., Yunes, R.A., Filho, V.C., Maia, A.A., De Souza, M.M., Niero, R., Cytotoxic, hypoglycemic activity and phytochemical analysis of Rubus imperialis (Rosaceae) (2002) Zeitschrift fur Naturforschung C, 57, pp. 272-276Kim, Y.H., Choi, J.H., Rim, H.K., Kang, H.J., Chang, S.G., Park, J.H., Park, H.J., Lee, K.T., 23-Hydroxytormentic acid and niga-ichigoside F1 isolated from Rubus coreanus attenuate cisplatin-induced cytotoxicity by reducing oxidative stress in renal epithelial LLC-PK, cells (2011) Biological Pharmaceutical Bulletin, 34, pp. 906-911Kreander, K., Galkin, A., Vuorela, S., Tammela, P., Laitinen, L., Heinonen, M., Vuorela, P., In-vitro mutagenic potential and effect on permeability of co-administered drugs across caco-2 cell monolayers of Rubus idaeus and its fortified fractions (2006) Journal of Pharmacy and Pharmacology, 58, pp. 1545-1552Krishna, G., Hayashi, M., In vivo rodent micronucleus assay: Protocol, conduct and data interpretation (2000) Mutation Research, 455, pp. 155-166Maistro, E.L., The in vivo rodent micronucleus test (2014) Genotoxicity and DNA Repair: A Practical Approach, Methods in Pharmacology and Toxicology, pp. 103-113. , L. María Sierra, Isabel Gaivão, Springer Science+Business Media New York, NYMann, J., Davidson, R., Hobbs, J., (1994) Natural Products. Their Chemistry and Biological Significance, , Longman Scientific Group, Essex, UKMeadows, A.T., Krejmas, N.L., Belasco, J.B., The medical cost of cure: Sequelae in survivors of childhood cancer. In: Van Eys, Sullivan, M.P (1980) Status of the Curability of Childhood Cancers, pp. 263-276. , Raven New York, NYMeadows, A.T., Baum, E., Fossati-Bellani, F., Green, D., Jenkin, R.D.T., Marsden, B., Nesbit, M., Voute, P.A., Second malignant neoplasms in children: An update from the late effects study group (1985) Journal of Clinical Oncology, 3, pp. 532-538Melin, C., Guimarães, K., Martin-Quintal, Z., Alves, A.D., Martins, D.T., Delle-Monache, F., Cechinel-Filho, V., Niero, R., Antimicrobial activity of extracts and fractions from aerial parts of selected plants (Garcinia achachairu, Macrosiphonia velame, Rubus niveus and Pilea microphylla) against some pathogenic microorganisms (2013) Natural Product Communications, 8, pp. 1567-1569Nam, J.H., Jung, H.J., Choi, J., Lee, K.T., Park, H.J., The anti-gastropathic and anti-rheumatic effect of niga-ichigoside F1 and 23-hydroxytormentic acid isolated from the unripe fruits of Rubus coreanus in a rat model (2006) Biological Pharmaceutical Bulletin, 29, pp. 967-970Niero, R., Cechinel-Filho, V., Souza, M.M., Montanari, J.L., Yunes, R.A., Delle-Monache, F., Antinociceptive activity of niga-ichigoside F1 from Rubus imperialis (1999) Journal of Natural Products, 62, pp. 1145-1146Novaes, A.P., Rossi, C., Poffo, C., Pretti-Júnior, E., Oliveira, A.E., Schlemper, V., Niero, R., Burger, C., Preliminary evaluation of the hypoglycemic effect of some Brazilian medicinal plants (2001) Therapie, 56, pp. 427-430(2001) Guideline for the Testing of Chemicals, No. 420: Acute Oral Toxicity - Fixed Dose Procedure, , OECD Organization for Economic Cooperation and Development Paris, FranceOliveira, P.F., Monteiro-Neto, M.A.B., Leandro, L.F., Bastos, J.K., Silva-Filho, A.A., Tavares, D.C., In vivo antigenotoxicity of Baccharin, an important constituent of Baccharis dracunculifolia DC (Asteraceae) (2011) Basic & Clinical Pharmacology & Toxicology, 109, pp. 35-41Patel, A.V., Rojas-Vera, J., Dacke, C.G., Therapeutic constituents and actions of Rubus species (2004) Current Medicinal Chemistry, 11, pp. 1501-1512Pfoze, N.L., Kumar, Y., Myrboh, B., Survey and assessment of ethnomedicinal plants used in Senapati District of Manipur State, Northeast India (2012) Phytopharmacology, 2, pp. 285-311Quiles, J.L., Huertas, J.R., Batino, M., Mataix, J., Ramirez-Tortosa, M.C., Antioxidants nutrients and adriamycin toxicity (2002) Toxicology, 180, pp. 79-95Ribeiro, J.C., Antunes, L.M.G., Aissa, A.F., Darin, J.D.C., De-Rosso, V.V., Mercadante, A.Z., Bianchi, M.L.P., Evaluation of the genotoxic and antigenotoxic effects after acute and subacute treatments with açai pulp (Euterpe oleracea Mart.) on mice using the erythrocytes micronucleus test and the comet assay (2010) Mutation Research, 695, pp. 22-28Richards, R.M., Durham, D.G., Liu, X., Antibacterial activity of compounds from Rubus pinfaensis (1994) Planta Medica, 60, pp. 471-473Schmid, W., The micronucleous test (1976) Mutation Research, 31, pp. 9-15Singh, H., Importance of local names of some useful plants in ethnobotanical study (2008) Indian Journal of Traditional Knowledge, 7, pp. 365-370Speit, G., Hartmann, A., The comet assay (single-cell gel test) (1999) Methods in Molecular Biology, 113, pp. 203-212. , D.S. Henderson, Humana Press Inc. Totowa, NJ (DNA Repair Protocols: Eukaryotic Systems)Srivastava, R.C., Singh, R.K., Community, A., Mukherjee, T.K., Indigenous biodiversity of Apatini plateu: Learning on biocultural knowledge of Apatini tribe of Arunachal Pradesh for sustainable livelihoods (2010) Indian Journal of Traditional Knowledge, 9, pp. 432-442Sultana, N., Akhter, M., Khatoon, Z., Nematicidal natural products from the aerial parts of Rubus niveus (2010) Natural Product Research, 24, pp. 407-415Tanira, M.O.M., Ali, B.H., Bashir, A.K., Wasfi, I.A., Chandranath, I., Evaluation of the relaxant activity of some United Arab Emirates plants on intestinal smooth muscle (1996) Journal of Pharmacy and Pharmacology, 48, pp. 545-550Thiem, B., Goslinska, O., Antimicrobial activity of Rubus chamaemorus leaves (2004) Fitoterapia, 75, pp. 93-95Uniyal, S.K., Singh, K.N., Jamwal, P., Lal, B., Traditional use of medicinal plants among the tribal communities of Chhota Bhangal, Western Himalayan (2006) Journal of Ethnobiology and Ethnomedicine, 2 (10). , (1186/1746-4269-2-14)Waters, M.D., Brady, A.L., Stack, H.F., Brockman, H.E., Antimutagenicity profiles for some model compounds (1990) Mutation Research, 238, pp. 57-8

High-performance Liquid Chromatographic Separation Of Rolipram, Bupivacaine And Omeprazole Using A Tartardiamide-based Stationary Phase. Influence Of Flow Rate And Temperature On The Enantioseparation

Chromatographic separation of the chiral drugs rolipram, bupivacaine and omeprazole on a tartardiamide-based stationary phase commercially named Kromasil CHI-TBB is shown in this work. The effect of temperature on the chromatographic separation of the chiral drugs using the Kromasil CHI-TBB stationary phase was determined quantitatively so as to contribute toward the design for the racemic mixtures of the named compound by using chiral columns. A decrease in the retention and selectivity factors was observed, when the column temperature increased. Van't Hoff plots provided the thermodynamic data. The variation of the thermodynamic parameters enthalpy and entropy are clearly negative meaning that the separation is enthalpy controlled. © 2007 Elsevier B.V. All rights reserved.11621 SPEC. ISS.97102Ding, G., Liu, Y., Cong, R.Z., Wang, J.D., (2004) Talanta, 62, p. 997Weng, W., Wang, Q.H., Yao, B.X., Zeng, Q.L., (2004) J. Chromatogr. A, 1042, p. 81Weng, W., Zeng, Q., Yao, B., Wang, Q., Li, S., (2005) Chromatographia, 61, p. 561Danel, C., Foulon, C., Park, C., Yous, S., Bonte, J.P., Vaccher, C., (2005) J. Sep. Sci., 28, p. 428Haroun, M., Ravelet, C., Ravel, A., Grosset, C., Villet, A., Peyrin, E., (2005) J. Sep. Sci., 28, p. 409Wang, P., Jiang, S., Liu, D., Jia, G., Wang, Q., Wang, P., Zhou, Z., (2005) Biomed. Chromatogr., 19, p. 454He, H., Liu, Y., Sun, C., Wang, X., Huy, C.P., (2004) J. Chromatogr. Sci., 42, p. 62Kang, G.W., Ko, J.H., Cheong, W.J., (2004) J. Liq. Chromatogr. Rel. Technol., 27, p. 595Rojkovičová, T., Lehotay, J., Krupčik, J., Fedurcová, A., Čižmárik, J., Armstrong, D.W., (2004) J. Liq. Chromatogr. Rel. Technol., 27, p. 1653Schlauch, M., Frahm, A.W., (2001) Anal. Chem., 73, p. 262Küsters, E., Spöndin, C., (1996) J. Chromatrogr. A, 737, p. 333Ahuja, S., (2000) Chiral Separations by Chromatography, , Oxford University Press, New YorkSilva Jr., I.J., Veredas, V., Carpes, M.J.S., Santana, C.C., (2005) Adsorption, 11, p. 123Skogsberg, U., Handel, H., Sanchez, D., Albert, K., (2004) J. Chromatogr. A, 1023, p. 215Peper, S., Lübbert, M., Johannsen, M., Brunner, G., (2002) Sep. Sci. Technol., 37, p. 2545Andersson, S., Allenmark, S.G., (2002) J. Biochem. Biophys. Methods, 54, p. 11Skogsberg, U., Allenmark, S., (2001) J. Chromatogr. A, 921, p. 161Johannsen, M., (2001) J. Chromatogr. A, 937, p. 135Andersson, S., Balmér, K., Persson, B., (1999) Chirality, 11, p. 420Löwendahl, A.C., Allenmark, S.G., (1997) Chirality, 9, p. 167Andersson, S., Allenmark, S.G., Möller, P., Persson, B., Sanchez, D., (1996) J. Chromatogr. A, 741, p. 23Garcia, A.L.L., Carpes, M.J.S., Oca, A.C.B.M., Santos, M.A.G., Santana, C.C., Correia, C.R.D., (2005) J. Org. Chem., 70, p. 1050Böcker, S., Mazzotti, M., Morbidelli, M., Fleury, C., Schenkel, B., (2002) Sep. Sci. Technol., 37, p. 172

Impact Of Drug Formulation And Free Platinum/cisplatin Ratio On Hypersensitivity Reactions To Cisplatin: Formulation Matters

What is known and objective Use of cisplatin can induce type I hypersensitivity reactions that may also be linked to the quality of the drug utilized. We observed cases of hypersensitivity that appeared to be associated with the brand of cisplatin used. The aim of this study was to compare two different brands of cisplatin in relation to type I hypersensitivity reactions. Methods Brand A was used in a tertiary care teaching hospital until 2012, and use of brand B started from January 2013, when the first hypersensitivity cases were observed. Patients were categorized based on symptom. Cisplatin of both brands was analysed by high-performance liquid chromatography (HPLC) and high-resolution electrospray ionization mass spectrometry (ESI-(+)-MS) and characterized according to US Pharmacopeia. Results and discussion There were no cases of hypersensitivity associated with the use of cisplatin brand A, whereas four of 127 outpatients that used cisplatin brand B were affected. The two brands were in accordance with the US Pharmacopeia parameters, and there was no significant difference in the total platinum levels between the two brands when analysed by HPLC. However, high-resolution ESI-(+)-MS analyses show that brand B contains approximately 2·7 times more hydrolysed cisplatin than brand A. What is new and conclusion The increase in the hydrolysed form of cisplatin found in brand B may be the cause of the hypersensitivity reaction observed in a subset of patients. We present the first study of the quality of drugs by high-resolution ESI-(+)-MS. Drug regulatory agencies and manufacturers should consider including measurement of hydrolysed cisplatin as a quality criterion for cisplatin formulations. Some cases of hypersensitivity that appeared to be associated with the brand of cisplatin used were observed. Increases in the hydrolyzed form of cisplatin found in brand B may be the cause of the hypersensitivity reaction observed in a subset of patients.4014147Rosenberg, B., Van Camp, L., Krigas, T., Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode (1965) Nature, 205, pp. 698-699Rosenberg, B., Van Camp, L., Trosko, J.E., Mansour, V.H., Platinum compounds: A new class of potent antitumour agents (1969) Nature, 222, pp. 385-386Reed, E., Cisplatin and its Analogs (2005) DeVita, Hellman and Rosenberg's Cancer: Principles & Practice of Oncology, p. 339. , De Vita V.T. Hellman S. Rosenberg S.A. eds. Philadelphia, PA: Lippincott Williams & WilkinsRabik, C.A., Dolan, M.E., Molecular mechanisms of resistance and toxicity associated with platinating agents (2007) Cancer Treat Rev, 33, pp. 9-23Weiss, R.B., Bruno, S., Hypersensitivity reactions to cancer chemotherapeutic agents (1981) Ann Int Med, 94, pp. 66-72Zweizig, S., Roman, L.D., Muderspach, L.I., Death from anaphylaxis to cisplatin: A case report (1994) Gynecol Oncol, 53, pp. 121-122Shlebak, A.A., Clark, P.I., Green, J.A., Hypersensitivity and cross-reactivity to cisplatin and analogues (1995) Cancer Chemother Pharmacol, 35, pp. 349-351Randall, J.M., Bharne, A.A., Bazhenova, L.A., Hypersensitivity reactions to carboplatin and cisplatin in non-small cell lung cancer (2013) J Thorac Dis, 5, pp. E53-E57Sakaeda, T., Kadoyama, K., Yabuuchi, H., Niijima, S., Seki, K., Shiraishi, Y., Okuno, Y., Platinum agent-induced hypersensitivity reactions: Data mining of the public version of the FDA Event Reporting System, AERS (2011) Int J Med Sci, 8, pp. 332-338Görög, S., Drug safety, drug quality, drug analysis (2008) J Pharm Biomed Anal, 48, pp. 247-253Bannister, S.J., Sternson, L.A., Repta, A.J., Urine analysis of platinum Species derived from cis-D1-chlorodiammineplatinum(II) by high-performance liquid chromatography following derivatization with sodium diethyldithiocarbamate (1979) J Chromatogr, 173, pp. 333-342Lopes-Flores, A., Jurado, R., Garcia-Lopes, P., A high-performance liquid chromatographic assay for determination os cisplatin in plasma, cancer cell, and tumor samples (2005) J Pharmacol Toxicol Methods, 52, pp. 366-372USP, (2013) USP29- NF24. Water, Method, p. 521. , Rockville, MD: US Pharmacopeial ConventionHunter, D., Milton, R., Perry, K.M.A., Asthma caused by complex salts of platinum (1945) Br J Ind Med, 2, pp. 92-98Saunders, M.P., Denton, C.P., O'Brien, M.E.R., Blake, P., Gore, M., Wiltshaw, E., Hypersensitivity reactions to cisplatin and carboplatin - A report on six cases (1992) Ann Oncol, 3, pp. 574-576Vogel, W.H., Infusion reactions: Diagnosis, assessment, and management (2010) Clin J Oncol Nurs, 14, pp. E10-E21Lenz, H.J., Management and preparedness for infusion and hypersensitivity reactions (2007) Oncologist, 12, pp. 601-609Goldberg, A., Altaras, M.M., Mekori, Y.A., Beyth, Y., Confino-Cohen, R., Anaphylaxis to cisplatin: Diagnosis and value of pretreatment in prevention of recurrent allergic reactions (1994) Ann Allergy, 73, pp. 271-272Bosch, M.E., Sánchez, A.J.R., Rojas, F.S., Ojeda, C.B., Analytical methodologies for the determination of cisplatin (2008) J Pharmacol Biomed Anal, 47, pp. 451-459Miller, R.P., Tadagavadi, R.K., Ramesh, G., Reeves, W.B., Mechanisms of cisplatin nephrotoxicity (2010) Toxins, 2, pp. 2490-2518Lippard, S.J., Chemistry and molecular biology of platinum anticancer drugs (1987) Pure Appl Chem, 59, pp. 731-742Makrilia, N., Syrigou, E., Kaklamanos, I., Manolopoulos, L., Saif, M.W., Hypersensitivity reactions associated with platinum antineoplastic agents: A systematic review (2010) Met-Based Drugs, 2010, p. 11Harford, C., Sarkar, B., Studies of induction of metallothionein in Jar (human choriocarcinoma) cells by cis and trans isomers of diamminedichloroplatinum (II) and their hydrolyzed species (1989) Mol Toxicol, 2, pp. 67-7