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Cisplatin is one of the well-established anticancer drugs being used against a wide spectrum of cancers. However, full therapeutic efficacy of the drug is limited due to development of various toxicities in the host. This study examines the comparative therapeutic effectiveness and toxicities of cisplatin alone and in combination of dietary ascorbic acid (AA) in ascites Dalton's lymphoma-bearing mice. The findings show that the combination treatment of mice with ascorbic acid plus cisplatin has much better therapeutic efficacy against murine ascites Dalton's lymphoma (DL) in comparison to cisplatin alone and this may involve a decrease in reduced glutathione (GSH), catalase activity and increased lipid peroxidation (LPO) in Dalton's lymphoma tumor cells. At the same time, combination treatment indicates a protective role of ascorbic acid against cisplatin-induced tissue toxicities (side effects) in the hosts. Cisplatin-induced histopathological changes in liver, kidney and testes were decreased after combination treatment. The analysis of renal function test (RFT), liver function test (LFT) and sperm abnormalities also suggest an improvement in these parameters after combination treatment. Therefore, it may be concluded that the increased GSH level, catalase activity and decreased LPO in the tissues, i.e., liver, kidney and testes after combination treatment may be involved in its protective ability against cisplatin-induced tissue toxicities in the host.

Phosphoenolpyruvate carboxykinase (PEPCK), a carboxylase enzyme is present in all living organisms. It catalyzes metal-nucleotide coupled reversible decarboxylation and phosphorylation between phosphoenolpyruvate (PEP) and oxaloacetate (OAA) depending on the system and the availability of the intermediates. In fungi, plants and in most bacteria, production of PEP from OAA by PEPCK is the key step during gluconeogenesis. In healthy human cytosolic PEPCK enzyme is present only during glucose starvation; cytosolic PEPCK rapidly disappears on the replenishment of glucose due to hormonal control of the transcription of the cytosolic PEPCK- gene. In some parasitic helminthes like Ascaris suum, nematodes such as Haemonchus contortus, PEPCK carry out the reverse reaction to produce OAA from PEP. In Trypanosoma cruzi and all species of the genus Leishmania, this enzyme is very active even in the presence of high level of carbohydrate. There is a significant functional difference between parasitic PEPCK and mammalian host PEPCK. These differences between the mammalian host and the parasite enzyme strongly support the belief that PEPCK should be further investigated as a possible target for selective chemotherapeutic agents. The experimental 3D structure of PEPCK of Schistosoma japonicum is not available in protein data bank. Therefore, based on the knowledge of the best template (3DT7), model of 3D structure of Schistosoma japonicum PEPCK was prepared using Modeller v9.10 software and processed in to energy minimization, Ramachandran plot analysis, quality assessment and characterization.

Cisplatin treatment caused a significant increase in the life span of ascites Dalton's lymphoma (DL) Tumor-bearing (TB) mice. However, as compared to cisplatin (CP) alone, combination treatment with ascorbic acid plus CP resulted in better therapeutic efficacy against murine DL. Cisplatin treatment of TB mice resulted in the appearance of thickened and irregular arrangement of mitochondrial cristae in the liver, kidney and DL tumor cells. Combination treatment of the hosts with ascorbic acid and CP lessened deformities in the mitochondria of liver and kidney, while in tumor cells, this increased the formation of vacuoles and disruption in mitochondrial cristae. Cisplatin treatment decreased the succinate dehydrogenase (SDH) activity in the mitochondria of kidney and DL cells and combination treatment caused further decrease in SDH activity in kidney and DL cells during 24-48 h of treatment. After CP treatment, the protein content in the mitochondria of these tissues decreased, and during combination treatment, it showed significant improvement. Mitochondrial lipid peroxidation (LPO) increased in these tissues after CP treatment. However, combination treatment significantly decreased mitochondrial LPO in liver and kidney but increased in DL cells. This increase in mitochondrial LPO in DL cells and decrease in liver and kidney could play an important role in the antitumor activity of combination treatment and at the same time reduce CP-induced toxicity in the host. However, further study may be desirable to explore some aspects of the mechanism(s) involved in these changes in mitochondria.

Changes in glutathione levels were determined in tissues of 11- to 12-week-old Swiss albino mice at different stages of Dalton's lymphoma tumor growth and following cisplatin (8 mg/kg body weight, ip) treatment for 24-96 h, keeping 4-5 animals in each experimental group. Glutathione levels increased in spleen of tumor-bearing compared to normal mice (9.95 +/- 0.14 vs 7.86 +/- 1.64 micromol/g wet weight, P

The public health effects of pesticides cannot be denied. However, the undesired effects of chemical pesticides have been recognized as a serious public health concern during the past decades. The present study describes the genotoxic effects of two pesticides, namely cypermethrin and carbosulfan, in a murine test system in vivo. The test parameter used was analysis of sister chromatid exchanges (SCE) in bone marrow cells. Both cypermethrin (5, 10 and 20 mg/kg) and carbosulfan (1.25, 2.5 and 5 mg/kg) induced significant increases in the frequency of SCEs (P < 0.001). However, no significant dose-response correlation could be found for either of the pesticides. Carbosulfan induced a cell cycle delay, as evidenced by an increase in average generation time accompanied by accumulation of cells in the first division cycle, but cypermethrin did not induce any such response. The present study indicates that carbosulfan has a higher potential to cause genetic alterations than cypermethrin in mice and may also pose a mutagenic risk to human beings.

The genotoxic effects of malathion was evaluated using chromosome aberration, sister chromatid exchange (SCE) and sperm abnormality assays in mice. All the three acute doses (2.5, 5 and 10 mg/kg) of malathion tested in the present study, induced significant dose-dependent increase in the frequency of chromosome aberrations and sperm abnormalities, but did not affect the total sperm count. The highest acute dose induced a >12-fold increase in the frequency of chromosome aberrations, two-fold increase in the frequency of SCEs and four-fold increase in the frequency of sperms with abnormal head morphology following intraperitoneal (i.p.) exposure. Further, a significant increase in the frequency of SCEs was observed, but the increase was not dose-dependent. At higher doses, malathion induced a moderate delay in cell cycle as evident from the increase in average generation time (AGT). The present findings suggest that technical grade malathion is a potent genotoxic agent and may be regarded as a potential germ cell mutagen also.

Malathion, a commonly used insecticide, is reported to be genotoxic in various test systems both in vivo and in vitro. However, no report on its genotoxic activity in avian test system could be found. In the present study, the genotoxic potential of technical grade malathion was investigated in chick in vivo. Malathion (2.5, 5, 10 mg/kg) induced significant dose-dependent increase in the frequency of micronuclei (MN) in the bone marrow cells following i.p. as well as p.o. routes of exposure. A significant decrease in mitotic index (MI) was observed for the highest dose (10 mg/kg) tested. In the peripheral blood cells, significant increase in the frequency of MN could be observed for the higher doses (5, 10 mg/kg) tested. Our results indicate that technical grade malathion may be considered as a mutagenic compound in chicks and is cytotoxic at higher doses.

The effect of cisplatin on five glutathione-related enzymes was studied in liver, kidney, and Dalton lymphoma cells of tumor-bearing mice. In liver, the activities of glutathione S-transferase, glutathione peroxidase, catalase, and superoxide dismutase decreased approximately 30-40%, 60-67%, 35-50% and 70-80% respectively, while glutathione reductase increased about 36-45% after cisplatin treatment. In kidney, catalase activity decreased by 47-82% at all time points (24-96 h) of cisplatin treatment, while glutathione S-transferase activity decreased significantly (approximately 24%) mainly at 72 h of treatment. An increase in glutathione reductase (approximately 1.5-2.5 times), glutathione peroxidase (significant at 24 h, 47%), and superoxide dismutase (approximately 15-60%) was noted in kidney after the treatment. In Dalton lymphoma cells, the activities of glutathione S-transferase, glutathione peroxidase, and catalase decreased very distinctly (approximately 2-5, 2-5 and 5-11 times, respectively) at all time points, but glutathione reductase decreased significantly only at 72 h of cisplatin treatment. Interestingly, the superoxide dismutase activity in Dalton lymphoma cells increased initially at 24-48 h and then decreased (approximately 60%) during later periods (72-96 h) of treatment. Cisplatin treatment caused a decrease in glutathione level in Dalton lymphoma cells (approximately 14-20%) and kidney (approximately 18-28%) but no change in liver. In view of the results, a definite correlation with the changes in glutathione concentrations and enzymatic activities in a tissue could not be firmly derived. It is suggested that the changes in various glutathione-related enzymes and glutathione levels in the tissues of the host during cisplatin-mediated chemotherapy could affect cellular antioxidant defense potential, which may play an important contributory role in cisplatin-mediated toxicity, particularly nephrotoxicity, and anticancer activity in the host.

The involvement of glutathione, a major cellular antioxidant, in cisplatin-mediated development of various hematological changes in mice bearing ascites Dalton lymphoma tumor was investigated. With tumor growth, glutathione levels decreased in blood but increased in tumor cells. Cisplatin treatment of tumor-bearing mice caused a decrease in glutathione levels in blood, ascites supernatant, and tumor cells. Blood hemoglobin, erythrocytes, packed cell volume and leukocytes (eosinophils, basophils, and lymphocytes) were also decreased along with the development of various morphological abnormalities in erythrocytes (microcytes, macrocytes, echinocytes, acanthocytes, etc.) after cisplatin treatment. All these hematotoxic features were noted to be increased more when buthionine sulfoximine (a specific glutathione-depleting agent) was also given prior to cisplatin treatment. However, combination treatment of cysteine (precursor for glutathione synthesis) plus cisplatin resulted in an improvement in the glutathione levels and decrease in hematological toxicities. It is noted that the glutathione levels in blood and abnormalities in erythrocytes and other hematological parameters are inversely related in cisplatin-mediated cancer chemotherapy. It is suggested that blood glutathione may play an important role in the development of cisplatin-mediated hematological toxicity in the host.

Cisplatin treatment of tumor-bearing mice resulted a significant decrease of protein in the tissues studied (liver, kidney, and Dalton lymphoma) and also in their mitochondrial fractions. As compared to respective tissues, the protein decrease was noted to be more conspicuous in their mitochondrial fractions. Similarly, mitochondrial glutathione also decreased significantly in the tissues. However, succinate dehydrogenase activity was selectively decreased in the kidney and Dalton lymphoma cells, whereas in liver it remained almost unchanged. An increase in serum urea concentration and kidney mitochondrial lipid peroxidation was also observed after cisplatin treatment. It is suggested that the cisplatin-induced biochemical changes in mitochondria involving mitochondrial protein, glutathione, and succinate dehydrogenase could be the important potent cellular sites contributing to toxicity/cytotoxicity after cisplatin treatment.

Lactate dehydrogenase (LDH) activity and its isozyme patterns were determined in various tissues of normal, Dalton's lymphoma (DL) bearing and cisplatin treated tumorous mice. Tumorbearing hosts showed about two fold higher serum LDH activity than that in the normal animals and following cisplatin treatment (8 mg/kg body wt, i.p.) for 1-4. days, serum LDH activity further increased. In kidney, as compared to normal mice, there was no significant change in the enzyme activity in tumor bearing hosts, but liver LDH activity increased in tumorous condition. After cisplatin treatment overall 20-30% decrease in the activity was noted in kidney and liver, with slight increase on the day 2 of treatment. LDH isozyme analysis revealed that in serum and kidney, all the five isozyme constituents were present, whereas, in liver and ascites tumor supernatant only LDH-3, -4 and-5 were observed with the predominance of LDH-5. In liver, after cisplatin treatment LDH-3 and-4 expression gradually decreased. In DL cells, LDH-5 was the only isozyme form present and after cisplatin treatment its activity increased.Thus, it is suggested that LDH activity is definitely affected in the tissues of tumor bearing hosts and during tumor regression after cisplatin treatment. The changes in LDH activity could be very useful parameter in malignancy and cisplatin-mediated chemotherapy against murine Dalton's lymphoma in particular and cancer in general. LDH isozyme patterns revealed the presence of tissue specificity of different isozymes, with only LDH-5 in tumor cells and appearance of some specific isozyme variant, named here as LDH-T, in the serum of tumor bearing hosts.

In present studies the development of chromosomal aberrations, micronuclei in bone marrow cells and sperm head abnormalities were used as mutagenic bioassay in Swiss albino mice treated with cisplatin alone or ascorbic plus cisplatin. It was noted that in the combined treated hosts the frequency of all the mutagenic parameters were always significantly less than that treated with cisplatin alone. These findings suggest a protective role of ascorbic acid against cisplatin induced mutagenic potentials. Interestingly, in combined treated hosts glutathione (GSH) level in bone marrow cells increased significantly which may suggest a possible mechanism of ascorbic acid mediated protection against cisplatin induced mutagenic potentials in the hosts.

Chromosome studies of Dalton's lymphoma (DL) revealed only one rb-marker in the cells and the chromosome numbers varied between 59 and 68 with a peak at 66 chromosomes. Thus, the modal number of chromosomes of this DL is suggested to be 66. Cisplatin treatment of tumor bearing hosts resulted the regression of the tumor and induced the formation of chromosomal aberrations/aberrant metaphases (80-90%) in the DL cells which may be responsible for the anticancer activity of cisplatin. Cisplatin treatment of the hosts caused the significant decrease in GSH levels in DL as well as bone marrow cells. Cisplatin's mutagenic potentials in the host is also supported from the observation of the induction of chromosomal aberrations in the bone marrow cells of the same host. Differential effect of cisplatin on the chromosomes of bone marrow and Dalton's lymphoma cells is noted. Bone marrow cells developed significantly less aberrant metaphases as compared to that of DL cells after cisplatin treatment in vivo. Interestingly, aberrant metaphases in bone marrow cells decrease appreciably with time of treatment (48-96 hr) which may suggest the possibility of an efficient clearance/repair of Pt-DNA adducts in bone marrow cells but in DL cells it remained more or less constant.

Cantharidin, a type of terpenoid, is the blistering agent of blister beetles frequently used in traditional medicine. The isolation and anticancer activity of cantharidin from blister beetles,Mylabris cichoriihas been recently reported by us. This study deals with changes in mitochondrial structure and function and understanding their significance in the underlying mechanism(s) in cantharidin-mediated antitumor effects in Dalton's lymphoma (DL) bearing mice. Cantharidin treatment caused the appearance of abnormal mitochondrial features which included roundish mitochondria with thickened membranes, irregularity in cristae, and appearance of small and large size vacuoles in mitochondria of DL cells. Cantharidin treatment resulted in a decrease in mitochondrial reduced glutathione, succinate dehydrogenase activity, mitochondrial membrane potential, and induced apoptosis and necrosis in DL cells. The decrease/release of mitochondrial cytochrome c were also observed after cantharidin treatment. Flow cytometry-based cell cycle analysis showed a time-dependent accumulation of the sub-G0 population of DL cells, thus, confirming the involvement of apoptosis in tumor cells in cantharidin-mediated antitumor activity. These finding signify that the apoptosis induced by cantharidin in DL cells should involve mitochondrial-dependent pathways. It is suggested that these cantharidin-mediated changes in mitochondria may play a crucial role in its antitumor activity.

Ethnopharmacological importance The blister beetles Epicauta hirticornis and Mylabris cichorii are used as a folk medicine by the Karbi tribe in Karbi Anglong district of Assam, India for the treatment of different human ailments, including cancer cases. Aim of the study It includes field survey related to zoo-therapeutic aspects of two blister beetles in Karbi community, isolation of bio-active compound and evaluation of its antitumor potential with possible mode of action against murine Ehrlich ascites carcinoma (EAC). Materials and methods The main bio-active compound of blister beetles was isolated from ethyl acetate extract and the structure was confirmed as cantharidin using NMR, IR, Mass and X-ray diffractometer. The effect of cantharidin on apoptosis, necrosis, autophagy and the apoptosis related signaling pathways were determined using different bioassays, including cell cycle analysis, mitochondrial membrane potential, western blot analysis of cytochrome c, caspases 9, 3/7 assays, and lactate dehydrogenase (LDH) assay. Results Cantharidin induced apoptosis, necrosis and autophagy cell death in EAC cells. The decrease in mitochondrial membrane potential was observed, which may help to release cytochrome c from mitochondria to cytosol. Cantharidin treatment caused up-regulation of caspases 9 and −3/7 and a decrease in LDH activity in EAC cells. Conclusion The major bioactive compound of these blister beetles is cantharidin which induces severe apoptosis in EAC cells involving mitochondrial intrinsic pathway. Cantharidin-mediated inhibition of LDH activity may lead to short supply of NAD+ and cut off energy and anabolic supply to cancer cells.

The present work describes the anticancer activity of cantharidin isolated from red-headed blister beetles, Epicauta hirticornis and its possible mode of action involving induction of apoptosis, oxidative stress and decrease in glutathione against murine ascites Dalton's lymphoma. The structure of isolated compound was confirmed as cantharidin by X-ray diffraction method. Cantharidin treatment showed potent anticancer activity with an increase in life span (~ 87%) of tumor-bearing mice. Cantharidin treatment induced apoptosis in Dalton's lymphoma cells and also caused an oxidative stress due to generation of reactive oxygen species (ROS) and an increase in lipid peroxidation. The observed canthardin-mediated decrease in glutathione and glutathione related enzymes activities in the tumor cells may weaken the cellular antioxidant system. Moreover, cantharidin treatment also caused a significant decrease in mitochondrial cytochrome c and simultaneous increase in cytosolic cytochrome c which ultimately facilitates activation of caspase 9 and 3 to augment mitochondrial apoptotic pathway causing cancer cell death. Based on the present findings, it may be suggested that cantharidin-mediated anticancer activity could be due to decrease in the protective ability of cancer cells by ROS and subsequent activation of effecter caspases leading to apoptotic cell death.

The anticancer activity of the extract of blister beetle, Mylabris cichorii has been documented earlier by us. In the present study, the active principle of M. cichorii was isolated and its anticancer efficacy was evaluated against murine Ehrlich ascites carcinoma (EAC). The isolated bioactive compound was characterized to be cantharidin which showed potent antitumor activity and inhibited the proliferation of Ehrlich ascites carcinoma, both in vivo and in vitro. Cantharidin-treated EAC-bearing mice showed about 82% increase in lifespan at the dose of 0.5 mg/kg/day. In vitro cytotoxicity assay with the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test revealed about 50% cell death at the concentration of 25.8 μg/ml. The fluorescence and transmission electron microscopy revealed that EAC cells treated with cantharidin depicted typical apoptotic morphology with chromatin condensation, nuclear fragmentation into discrete masses, and plasma membrane blebbing which deduce towards the death of these cells. Histological examination of the kidney of cantharidin-treated mice showed glomerular and tubular congestion with abnormal Bowman’s capsule, thus, indicating a renal toxicity in the host. Cantharidin-induced renal damage in the host was also manifested by the decreased lactate dehydrogenase isozymes and its possible release from the cells.

Cantharidin, a type of terpenoid, is a blistering agent of most of the blister beetles. The isolation and antitumor activity of cantharidin from blister beetles, Mylabris cichorii has been recently reported by us [4]. This study aim at to study the ultrastructural changes in mitochondria with their function and understanding their significance in the underlying mechanism associated with cantharidin-mediated antitumor effects in Dalton’s lymphoma (DL) bearing mice which is not yet reported. Transmission electron microscopic (TEM) study after cantharidin treatment (0.5mg/kg) in DL bearing mice caused the appearance of abnormal mitochondrial features (Fig. 1) which included roundish mitochondria with thickened membranes, irregularity in cristae, and appearance of small to large size vacuoles in mitochondria of DL cells. As compared with the corresponding control, cantharidin-treated mice also showed a significant time dependent decrease in succinate dehydrogenase (SDH) activity in the mitochondria of DL cells moreover, molecular docking study also showed strong interaction with cantharidin in SDH active site (Fig 4). The ampholytic cationic fluorescent probe rhodamine-123 was used to monitor cantharidin-induced changes in the mitochondrial transmembrane potential using flow cytometry and the result showed cantharidin-mediated time-dependent shifting of mitochondrial fluorescence intensity toward the left indicating a decrease in mitochondrial membrane potential (Fig. 3). Cantharidin treatment also induced apoptosis (69%), necrosis (8%) and autophagy (12%) in DL cells after 96h of treatment (Fig. 2). The apoptotic morphological features using confocal microscopy based study reflects cell shrinkage, cytoplasmic condensation, DNA fragmentation and membrane blebbing; whereas necrosis involves loss of membrane integrity, cell swelling, formation of cytoplasmic vacuoles, swollen endoplasmic reticulum and ruptured mitochondria while autophagy cells shows the formation of autophagosomes that engulf cellular macromolecules and organelles, leading to their breakdown, following fusion with lysosomes. Flow cytometry-based cell cycle analysis showed a time dependent accumulation of the sub-G0 population of DL cells, thus, confirming the involvement of apoptosis in tumor cells in cantharidin-mediated antitumor activity. Based on the result of present study it may be suggested that these cantharidin-mediated changes in mitochondrial structure and function may play a crucial role in its antitumor activity.

Cyclophosphamide, an antineoplastic drug effective against a wide variety of cancers is cytotoxic to normal cells also. Ascorbic acid (vitamin C) at higher concentrations possesses cytotoxic effects and it can also enhance the cytotoxicity of 5-fluorouracil in a dose-dependent manner in mouse lymphoma. In the present study, effect of cyclophosphamide treatment alone and in combination with ascorbic acid in vivo on the ultrastructure and some biochemical changes in Dalton's lymphoma tumor cells were investigated. Cyclophosphamide treatment causes disappearance of cell membrane processes, thickening and reduction in the number of mitochondrial cristae as well as the manifestation of rounded shape of mitochondria. The combination treatment with ascorbic acid plus cyclophosphamide caused further changes in tumor cells showing disintegration in the cell surface membrane, disruption in the nuclear membrane and roundish mitochondria with reduction and disruption in the mitochondrial cristae. The observed ascorbic acid plus cyclophosphamide-mediated decrease in reduced glutathione (GSH) in tumor cells may play an important role in the antitumor activity of cyclophosphamide by weakening cellular antioxidant-mediated defense mechanism, thereby increasing tumor cell's susceptibility to cell death. The cyclophosphamide-mediated decrease in lactate dehydrogenase activity in tumor cells and simultaneous increase in ascites supernatant may possibly indicate alteration in the membrane permeability of tumor cells for lactate dehydrogenase as well as tumor cell injury. Further investigation should determine detailed mechanism(s) involved in cyclophosphamide-induced ultrastructural and biochemical changes in tumor cells.

Cisplatin treatment of tumor-bearing mice and analysis of ultrastructural features of mitochondria in the kidney and Dalton's lymphoma cells showed the appearance of more roundish mitochondria with thickened membranes. It also caused the reduction in the number and irregularity in the shape of cristae and formation of vacuoles in the mitochondria. After cisplatin treatment, decreased level of protein, succinate dehydrogenase activity, and increased level of lipid peroxidation were noted in Dalton's lymphoma tumor cells and kidney. Cisplatin-mediated decrease in SDH activity, GSH level and an increase in LPO in the mitochondria of kidney could play an important role to produce nephrotoxicity. However, in DL cells, decrease in cellular GSH could be noteworthy than mt-GSH, along with decrease in SDH activity and increase in LPO in the cisplatin-mediated anticancer activity. These changes could play an important role to produce both the cisplatin-mediated effects i.e. anticancer activity and nephrotoxicity. Cisplatin-induced biochemical and ultrastructural changes in mitochondria after cisplatin treatment should be an important factor in the development of biochemical injury in mitochondria and affecting the overall metabolism in the cells. The findings from the present studies indicate multilevel effect of cisplatin in the cells and do support the earlier view that mitochondria could be a critical target in cisplatin-mediated anticancer activity and toxicity in the hosts.

cis-Diaminedichloroplatinum(II), commonly known as cisplatin, treatment of mice for 24-96, 30 h and 10 days caused the development of chromosomal aberrations in bone marrow cells as well as in Dalton's lymphoma (DL) cells, micronuclei (MN) in bone marrow cells and abnormalities in sperm heads, and it indicates the genotoxic potential of cisplatin in the host. Cisplatin exerts differential effects on the chromosomes of the bone marrow and tumor cells. Combination treatment of cisplatin with L-buthionine(S,R)-sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, enhanced these cisplatin-induced genotoxic effects, but supplementing glutathione level with cysteine, its precursor, reduced the cisplatin-induced genotoxicity. The reduction in cellular glutathione level may facilitate increased intracellular accumulation and binding of drug to DNA to enhance the frequency of genotoxicity parameters. These findings support the possible involvement of glutathione as an important intracellular protective agent and suggest that differences in its levels may be one of the factors in the varying sensitivity of cells to cisplatin-induced genotoxic effects in the mice bearing ascites Dalton's lymphoma.

Fenvalerate, a synthetic pyrethroid insecticide, is commonly used in agriculture and other domestic applications due to its high insecticidal activity and low mammalian-, avian- and phyto-toxicities. However, the genotoxic effect of fenvalerate is highly equivocal. In the present study the genotoxic effects of fenvalerate was evaluated using structural chromosome aberration (CA) and sister chromatid exchange (SCE) assays in mice. Out of the three doses (5, 10 and 20 mg/kg) tested, statistically significant increase in CA was found following intra peritoneal (i.p.) treatment of 2 0 mg/kg of fenvalerate for 24 h (P0.01) and 48 h (P0.05) only. Neither the acute doses of 5 and 10 mg/kg, nor the sub-acute dose (5x4 mg/kg) of fenvalerate could induce any significant effect. All the three acute doses induced significant increase in the frequency of SCEs (P0.01) in the bone marrow cells, which showed a significant dose-response correlation (r=0.9541, P0.05). With certain reservations to possible impurities, from the present findings technical grade fenvalerate may be considered as a weak clastogen and a potent inducer of SCEs in mice.

The genotoxic effects of carbosulfan were evaluated using chromosome aberration (CA), bone marrow micronucleus (MN) and sperm abnormality assays in mice. All the three acute doses (1.25, 2.5 and 5mg/kg) of carbosulfan induced significant dose-dependent increase in the frequency of CA (P0.02), micronucleated polychromatic erythrocytes (PCEs) (P0.05) and sperm head abnormalities (P0.05) but did not affect the total sperm count. The highest acute dose of carbosulfan induced7-fold increase in the frequency of CA,3.5-fold increase in the frequency of micronucleated PCEs and4.6-fold increase in the frequency of sperms with abnormal head morphology following intraperitoneal exposure as compared to the untreated controls. The present findings suggest that carbosulfan is a potent genotoxic agent and may be regarded as a potential germ cell mutagen also.

In this paper we report the effect of cis-dichlorodiammine platinum(II) (cis-platin) on the agglutination of normal and transformed lymphocytes with lectins conconavalin A (Con A) and wheat germ agglutinin (WGA) which is a sensitive test to study the expression of cell surface components. Normal splenocytes showed small degree of cell agglutination with Con A and WGA. This cell agglutination of normal splenocytes with these lectins increases significantly after cis-platin treatment at 37 degrees C. The Dalton's lymphoma cells which show a high degree of cell agglutination with Con A and WGA when treated with cis-platin at 37 degrees C results in decrease in the degree of their cell agglutination with these lectins. Agglutination inhibition studies with alpha-methyl-D-glucopyranoside for Con A and N-acetyl-D-glucosamine for WGA shows that this increase and decrease of cell agglutination after platinum treatment of cells is a specific reaction and not non-specific. Incubation of cis-platin treated normal splenocytes with excess of neuraminic acid results in decrease of cell agglutination with both Con A and WGA. cis-Platin treatment of the cells results in the release of sialic acid from the surface of the cells. A correlation between the release of sialic acid from the cell surface and cell agglutination is also discussed.