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Biomedical subjects

K P Gupta

Publications and source records attributed to K P Gupta.

At least 19 recordsLinked to original sources
PubMed1992

Status of ornithine decarboxylase activity and DNA synthesis in mancozeb-exposed mouse skin.

The effect of mancozeb, a fungicide, on mouse skin ornithine decarboxylase (ODC) activity and DNA synthesis was studied. ODC activity was induced after topical application of mancozeb and exhibited a peak level at 5 h. This ODC induction was dependent on the dose of mancozeb applied. Cycloheximide, an inhibitor of protein synthesis, inhibited the mancozeb-caused ODC induction, indicating the effect on enzyme protein synthesis. The rate of DNA synthesis was also increased by mancozeb, as indicated by increased [3H]thymidine incorporation into skin DNA. Induction of ODC activity and DNA synthesis are among the events probably involved in the tumorigenic action of mancozeb on mouse skin.

Animals↗
PubMed1991

Inhibition of mouse skin tumor promotion by tenuazonic acid.

Tenuazonic acid (TA) was topically applied to the interscapular region of Swiss albino mice at different doses before the application of 12-O-tetradecanoyl phorbol-13-acetate (TPA). Skin from the painted area was examined for ornithine decarboxylase (ODC) enzyme estimation. It was observed that TA inhibited TPA induced ODC activity. The inhibitory effect of TA was also found in mouse skin tumor promotion in the two stage initiation promotion protocol. There was a remarkable delay in the latency period and decrease in the number of tumors developed and the percentage of tumor bearing animals after TA treatment.

Administration, Topical↗
PubMed1991

Transient enhancement of multidrug resistance by the bile acid deoxycholate in murine fibrosarcoma cells in vitro.

Recent studies have implicated protein kinase C (PKC) activation in drug resistance in vitro. PKC can be activated directly by phorbol-ester tumor promoters as well as by the bile acid deoxycholate. In this report, we demonstrate that deoxycholate, at concentrations that are chronically present in the lumen of the colon in vivo, mimicked phorbol-ester tumor promoters by protecting Adriamycin (ADR)-sensitive and multidrug-resistant (MDR) murine fibrosarcoma UV-2237M cells from ADR cytotoxicity. Deoxycholate also enhanced the resistance of the MDR cell line UV-2237M-ADRR to the cytotoxic effects of vincristine and vinblastine. In contrast to cytotoxic drug-selected MDR phenotypes, deoxycholate-induced drug resistance was transient and required continuous exposure to the bile acid. The protein kinase inhibitor H7 completely reversed the protection against ADR cytotoxicity conferred on UV-2237M-ADRR cells by deoxycholate, providing evidence that deoxycholate exerts its protective effects by a mechanism that involves stimulation of protein phosphorylation and not merely by detergent effects on membrane permeability. PKC consists of a family of at least seven isozymes with distinct modes of activation and substrate specificities. We previously reported that MDR UV-2237M cell lines contain higher levels of PKC activity than the parental ADR-sensitive UV-2237M cell line (O'Brian et al., FEBS Lett 246: 78-82, 1989). The present report shows that PKC-III is a major PKC isozyme in ADR-sensitive and MDR UV-2237M cell lines. Thus, the resistance to ADR induced by the phorbol esters in UV-2237M cell lines provides strong evidence that PKC-III activation confers protection against ADR on ADR-sensitive and MDR UV-2237M cell lines. Furthermore, since deoxycholate is an endogenous molecule in the colonic epithelium, our finding that physiological concentrations of deoxycholate can render cells more resistant to chemotherapeutic drugs in vitro may have implications for the biology and therapy of intestinal cancers.

Animals↗
PubMed1991

In vitro model for intrinsic drug resistance: effects of protein kinase C activators on the chemosensitivity of cultured human colon cancer cells.

We investigated the effects that phorbol ester and diacylglycerol protein kinase C (PKC) activators had on the chemosensitivity of the human colon cancer cell line KM12L4a to Adriamycin (ADR), vincristine (VCR), and vinblastine (VLB) and on the intracellular accumulation of those drugs. Exposure of the cells to the PKC activator phorbol-12,13-dibutyrate (PDBu) (15 nM) during a 96-hr in vitro chemosensitivity assay significantly reduced the sensitivity of KM12L4a cells to ADR, VCR, and VLB, but not to 5-fluorouracil. Because a 96-hr treatment with 15 nM PDBu did not down-regulate PKC activity in KM12L4a cells, activation of PKC appeared to be responsible for the observed protection conferred by PDBu. PDBu-induced alterations in drug accumulation may account for its protective effects against these cytotoxic drugs, because both PDBu and the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate significantly reduced accumulation of [3H] VCR and [14C]ADR in the cultured human colon cancer cells. Unsaturated diacylglycerols are structural and functional analogues of phorbol ester PKC activators that are present in the lumen of the colon. We found that treatment of KM12L4a human colon cancer cells with the diacylglycerol 1-oleoyl-2-acetyl-sn-glycerol (OAG) significantly reduced [14C]ADR and [3H]VCR accumulation in the cells. The effects of OAG were dose dependent at physiological diacylglycerol concentrations and were completely reversed by the protein kinase inhibitor H7. OAG, which is rapidly metabolized in cultured cells, did not protect KM12L4a cells against the cytotoxic drugs in our 96-hr in vitro chemosensitivity assay. However, rapid metabolism of diacylglycerols should not limit their capacity to activate PKC in the colonic epithelium in vivo, because that tissue is chronically exposed to replenished supplies of unsaturated diacylglycerols in the intestinal tract. Our results provide evidence that unsaturated diacylglycerols may be environmental factors that contribute to the intrinsic drug resistance of colon cancer in vivo by reducing drug accumulation in the cancer cells.

Antineoplastic Agents↗
PubMed1990

Site-dependent differences in response of the UV-2237 murine fibrosarcoma to systemic therapy with adriamycin.

Murine fibrosarcoma UV-2237MM cells were implanted into different organs of syngeneic C3H/HeN mice. The resultant tumors were treated by i.v. administration of Adriamycin (ADR). Despite the high sensitivity of the fibrosarcoma cells to ADR in vitro, the established tumors growing in vivo exhibited marked differences in their responses to ADR. Tumors growing in the subcutis and the spleen were ADR-sensitive, whereas lung metastases were not. The resistance of lung metastases to ADR was not due to selection of a drug-resistant population since tumor cells isolated from lung metastases were highly sensitive to ADR under in vitro conditions. The responsiveness of skin and spleen tumors to ADR was due neither to increased blood supply nor to preferential accumulation of ADR, since both parameters were higher in lung metastases. Protein kinase C activity levels correlated with ADR resistance in the closely related murine fibrosarcoma cell line UV-2237 and its ADR-selected multidrug-resistant variants. However, nearly identical levels of protein kinase C activity were found in UV-2237MM tumors growing in the lung, spleen, and subcutis, indicating that protein kinase C activity levels did not account for the different responses to ADR. The present studies suggest that the organ environment influences the response of UV-2237MM to ADR administered systemically. This finding may have implications for the design of animal models for therapy of disseminated cancer.

Animals↗
PubMed1990

Mouse skin ornithine decarboxylase induction and tumor promotion by cyclohexane.

Cyclohexane, a frequently used solvent in industry, was assessed for its tumorigenic potential on mouse skin following multistage initiation-promotion protocols. The activity of ornithine decarboxylase (ODC), a marker of tumor promotion was found to be induced by the topical application of cyclohexane. This ODC induction was dependent on the dose of cyclohexane used and the duration of application. Effect of protein synthesis inhibitors and the modifiers of tumor promotion on the cyclohexane induced ODC activity was also studied. ODC induction was inhibited by cycloheximide and also, up to some extent, by actinomycin D. Inhibitors of stage II tumor promotion showed more effect on the ODC induction by cyclohexane as compared to the inhibitors of stage I tumor promotion. In chronic animal bioassay experiments topical application of cyclohexane to DMBA initiated mouse skin resulted in just 10% of tumor bearing animals while prior application of TPA for two weeks resulted in 45% of tumor bearing animals. Collectively, the present study demonstrates that cyclohexane is more effective as a stage II tumor promoter over mouse skin and possibly affects the biochemical events at the molecular level.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Age-dependent covalent DNA alterations (I-compounds) in rat liver mitochondrial DNA.

Rat liver mitochondrial (mt) DNA was investigated for the presence of I-compounds, a recently discovered type of DNA modifications which is detected and measured via 32P-postlabeling. These DNA modifications were previously shown to accumulate in an age-dependent manner in total cellular DNA of various tissues of untreated rodents. In the present work, mt DNA of 1-, 3-, 6-, and 9-month-old female Sprague-Dawley rats was found by 32P-postlabeling also to contain I-compounds that increase with age. Most of the I-compounds were identical for mt and nuclear (nu) DNA. A cluster of 2 non-polar I-spots (termed M-compounds) was mitochondria-specific and increased about 8-fold from 1 to 9 months, attaining a RAL value of 44 X 10(-9) or 1 modification in 2.3 X 10(7) DNA nucleotides at 9 months. Quantitative differences between chromatographically identical spots were seen mainly for a low-polarity fraction of I-compounds, which exhibited 2 times higher overall levels in mt DNA versus nu DNA over the age range studied. Total I-compound levels increased during this time 6.9- and 5.1-fold in nuclei and mitochondria, respectively. The M-compound level was close to 10% of total mt DNA I-compound levels. M-compounds may conceivably be derived from potentially DNA-reactive electron carriers of the mt electron-transport chain, while I-compounds common to both mt and nu DNA presumably originate in extramitochondrial sources. The similarity of mitochondrial and nuclear I-compound profiles and amounts implies possible regulatory mechanisms in I-compound formation and repair. Mt DNA maps showed additional 32P-labeled material which may have been associated with DNA damage caused by oxygen free radicals known to be generated by the mt electron-transport chain. Age-dependent increases of mt DNA modifications are potentially related to mt mutations and may be linked to age-related degenerative changes in mitochondria.

Aging↗
PubMed1989

Tumor initiation in mouse skin by cutting oils.

In order to study the skin tumor-initiating potential for fresh and used cutting oils, a chronic animal bioassay following an initiation-promotion protocol was performed. Tumor initiation was performed by topical application of a single dose of neat fresh/used cutting oil on the mouse skin. After a week, these animals were treated topically with 12-O-tetradecanoylphorbol 13-acetate (TPA), a potent skin tumor promoter. Repeated application of TPA resulted in the appearance of tumors almost at the same time (6-8 weeks) in the groups initiated with fresh or used cutting oil. After a prolonged application of TPA, for 28 weeks, it was observed that the cumulative number of tumors and tumor-bearing animals in the used oil initiated group was slightly less compared to that exposed to a fresh variety of oil. Histopathological examination of the tumors could not show any qualitative differences in the nature of tumors developed in both groups. It seems that both fresh and used cutting oils act as potent skin tumor initiators.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Acute toxicity of hexachlorocyclohexane (HCH) in mice, rats, rabbits, pigeons and freshwater fish.

Technical Hexachlorocyclohexane (HCH) is a mixture of several stereo isomers, whose percent content has shown wide variation in different samples. In spite of its importance and extensive use over the last 3 decades, basic information on acute toxicity of HCH in various species of animals seems to be either lacking or very fragmentary. The present report with information on acute toxicity of technical HCH in mice, rats, rabbits, pigeon and freshwater fish therefore has significance. The study examines the role of modulating factors, such as chemical composition of technical HCH with different isomers, the sex of animals, route of exposure and nature of the vehicle or solvent, in the overall characterization of HCH-induced toxicity.

Administration, Oral↗
PubMed1989

Dermal toxicity of hexachlorocyclohexane (HCH) in rabbit.

Application of HCH (25 mg/kg) on dorsal, ventral and thigh regions of the skin of male rabbits resulted in poisoning and mortality of animals. Morphological changes in skin, liver, kidney, testes and cerebellum together with highly significant alterations in serum and liver enzymatic activity and residue in blood suggested that absorption of HCH and its toxicity could be severe when the pesticide comes in contact with the skin of thigh region of body.

Animals↗
PubMed1988

Effect of repeated dermal application of endosulfan to rats.

Dermal application of endosulfan to male (18.75, 37.50 and 62.50 mg/kg/day) and female (9.83, 19.66 and 32.0 mg/kg/d) rats for 30 days produced hyperexcitability, tremor, dyspnea and salivation. There were no deaths. The signs of toxicity subsided after a week. Endosulfan produced no significant changes in the organ:body weight ratio. No significant changes were seen in the histological and hematological indices. However, a significant decrease in liver GOT and GPT and serum GPT activities and a significant rise in serum alkaline phosphatase and total protein were recorded in the endosulfan-treated animals. There were no changes in LDH. Residue analysis revealed higher levels of total endosulfan in fatty tissues of rats receiving the highest dose of endosulfan.

Animals↗
PubMed1987

Effect of butyric acid on 12-O-tetradecanoylphorbol-13-acetate-(TPA) induced mouse skin ornithine decarboxylase (ODC).

Butyric acid was topically applied on the interscapular region of Swiss albino mice before and after application of 12-O-tetradecanoylphorbol-13-acetate (TPA) in various doses and at different time intervals. Skin taken from the painted area, 4 h after TPA application, was subjected to ornithine decarboxylase (ODC) enzyme estimation. It was found that butyric acid inhibited the TPA-induced mouse skin ODC activity. The effect was dependent on the dose and duration of the butyric acid application.

Animals↗