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Biomedical subjects

R S Pardini

Publications and source records attributed to R S Pardini.

At least 55 records · Page 3Linked to original sources
PubMed1986

Heterotransplantation of equine carcinoma cells in athymic (nude) mice.

Nondifferentiated equine carcinoma cells from a primary lesion were implanted subcutaneously in athymic (nude) mice. The cells were implanted at 2 sites each in 3 mice. At 1 of the 6 inoculation sites, a tumor developed, which invaded surrounding tissues, as shown by histopathologic examination. Karyotype analysis verified that the tumor was of equine origin. Cells from this tumor were serially heterotransplanted 20 times without change in growth rate. Once established in nude mice, this equine carcinoma cell line was stored cryogenically and then was successfully reimplanted into nude mice. All of the implants developed into tumors, over 20 generations. Preliminary screening of antineoplastic drugs indicated that this tumor line is sensitive to cyclophosphamide. Because of its ease of handling and high reimplantation efficiency, this tumor line should prove useful in equine cancer research.

Animals↗
PubMed1984

A redox cycling mechanism of action for 2,3-dichloro-1,4-naphthoquinone with mitochondrial membranes and the role of sulfhydryl groups.

The addition of 2,3-dichloro-1,4-naphthoquinone (CNQ) to substrate-depleted, GSH-supplemented rat liver mitochondria resulted in a dose-dependent depletion of reactable suflhydryl groups and a concomitant increase in mitochondrial disulfide content at a ratio of 2 thiols depleted/disulfide generated. The molar ratio of thiol depleted/CNQ added approached 20 at low CNQ concentrations and was unity at higher doses. The addition of CNQ to substrate-depleted mitochondrial suspensions resulted in O2 consumption which increased with increasing concentrations of mitochondria and was sensitive to N-ethylmaleimide (NEM) which establishes the ability of CNQ to interact with mitochondrial thiol redox centers. The CNQ-mediated large amplitude swelling of rat liver mitochondria was exacerbated by thiol oxidizing agents and depressed by disulfide reducing agents. A redox cycling mechanism between mitochondrial thiol groups, CNQ and oxygen was proposed to lower the matrix glutathione pool and make the mitochondria more susceptable to toxic oxygen radicals which induce swelling in isolated mitochondrial suspensions. In support of this mechanism, alpha-tocopherol was shown to prevent the CNQ-mediated swelling process. Beef heart mitochondrial NADH was oxidized by CNQ in a 1/1 molar ratio anaerobically and in a 3/1 molar ratio under aerobic conditions, whereas the fully reduced quinone, CNQH2, oxidized NADH aerobically but not anaerobically. Thus, CNQ is capable of interacting with NADH of the mitochondrial electron transport chain in a redox cycling fashion.

Animals↗
PubMed1984

Anti-neoplastic activity of C205: a new topical anti-cancer formulation.

C205, a topical ointment currently in clinical trial, was tested by a method developed to evaluate the topical activity of new drugs. Subcutaneous B-16 melanoma was used as the primary tumor model. Tumor size of treated animals as percentage of tumor size of control animals (T/C ratio) was found to be 14, with 50% of the animals tested free of viable and palpable tumor at 60 days post treatment. The anti-neoplastic activity of C205 was superior to 5-fluorouracil using the same method of evaluation. Only minimal loss of animal body weight occurred after C205. C205 also showed anti-tumor activity against subcutaneously implanted Lewis lung carcinoma.

Acridines↗
PubMed1983

A role for glutathione disulfide as a scavenger of oxygen radicals produced by 2,3-dichloro-1,4-naphthoquinone.

The addition of 2,3-dichloro-1,4-naphthoquinone (CNQ) to isolated mitochondria supplemented with GSSG resulted in a respiratory burst with the production of O2- and H2O2, and a decrease in the level of measurable disulfide. Superoxide generated by the xanthine oxidase system or by CNQ-treated mitochondria caused the reduction of GSSG to GSH. Both disulfide reductions were partially sensitive to exogeneous SOD. GSSG was also shown to interfere with the epinephrine - adrenochrome superoxide assay system. The findings reported herein support the conclusion that GSSG is capable of scavenging O2- and has the potential to scavenge other free radicals by a similar mechanism.

Animals↗
PubMed1981

Characterization of 2,3-bis(chloromethyl)-1,4-naphthoquinone induced mitochondrial swelling.

Mitochondrial swelling induced by 2,3-bis(chloromethyl)-1,4-naphthoquinone (CMNQ) was found to be a non-energy linked, oxygen and sulfhydryl-dependent, substrate-independent, osmotic process, that lack cation specificity. Swelling was inhibited by cysteine and DTNB, and the CMNQ induced swelling resulted in a decrease in mitochondrial reactive sulfhydryl groups; thus, mitochondrial sulfhydryl interaction was mandatory in the CMNQ swelling process. The non-enzymatic reaction of CMNQ with cysteine but not cystine resulted in the consumption of oxygen, implicating sulfhydryl redox activity in the swelling process. High level of tocopherol and histidine depressed the CMNQ induced swelling, suggesting that free radicals and singlet oxygen are important in the CMNQ induced swelling process. These findings support the proposition that CMNQ interacts with mitochondrial reductase systems and sulfhydryl groups in such a way as to generate superoxide radical which subsequently may dismute to H2O2 and produce .OH and possibly singlet oxygen. These toxic oxygen species may be responsible for the CMNQ-promoted sulfhydryl depletion and mitochondrial swelling.

Alkylating Agents↗
PubMed1981

The inhibition by a series of potentially bioreductive naphthoquinones of rat liver mitochondria and sarcoma 180 tumor cell respiration.

A series of potentially bioreductive naphthoquinones were investigated for their effects on rat liver mitochondrial electron transport and energy transfer and their ability to inhibit Sarcoma 180 tumor cell respiration in vitro. It was found that all the naphthoquinones evaluated, inhibited tumor cell respiration and rat liver mitochondrial oxidative metabolism. It was also found that 1,4-naphthoquinones substituted at the 2 and 3 positions were more effective inhibitors of the respiratory and energy transfer systems studied than those substituted at the 2 position only. 2,3-bis(chloromethyl) 1,4-naphthoquinone was found to cause the most rapid onset of inhibition, cause an immediate burst of cyanide insensitive respiration, and cause a preferential reduction of cytochromes c, a and a3 following oxygen depletion.

Animals↗
PubMed1980

Toxicology of various pesticides and their decomposition products on mitochondrial electron transport.

The effect of various pesticides and derivatives on mitochondrial electron transport systems was assessed. DDT, DDE, TDE, Kelthane, chlorobenzilate, chloropropylate and Acarol were found to be inhibitory towards both heavy beef heart mitochondrial (HBHM) NADH-oxidase and succinoxidase enzyme systems. Dichlorobenzophenone and p-chlorophenol were less inhibitory towards the HBHM NADH-oxidase and did not inhibit the succinoxidase enzyme system. DDA did not inhibit either of the electron transport systems. Carbaryl was not inhibitory towards both HBHM oxidase systems, whereas its degradative product dihydroxynaphthalene was inhibitory at the same concentration. Furadan, Matacil, Baygon and Dimetilan were only slightly inhibitory towards themitochondrial NADH-oxidase system and did not inhibit the succinoxidase system. Zectran was inhibitory towards the NADH-oxidase system and was not inhibitory towards the succinoxidase system. DDT, DDE and TDE, dihydroxynaphthalene and 1-naphthol inhibited the NADH-oxidase enzyme system onthe substrate side of cytochrome c, whereas Kelthane inhibited on the oxygen side.

Animals↗
PubMed1979

Effects of the bioreductive alkylating agent 2,3-bis(chloromethyl)-1,4-naphthoquinone on coupled mitochondria isolated from sarcoma 180 ascites cells.

The effect of CMNQ was studied on mitochondria isolated from S-180 ascites tumor cells. It was found that the primary metabolic event upon addition of CMNQ to S-180 mitochondria was a stimulation of oxygen uptake. The oxygen utilization rate was maximized at about 50 nmoles CMNQ/mg protein; at doses higher than this, inhibition of respiration was observed relative to the stimulation of respiration produced by CCCP. It was also up to 50 nmoles CMNQ/mg protein. S-180 ATPase activity is stimulated maximally by 125 nmoles CMNQ/mg protein; at doses higher than this, slight inhibition of the ATPase activity relative to the stimulation produced by CCCP is seen. In vivo treatment of CMNQ to tumor bearing animals leads to a significant reduction of in vitro S-180 cellular respiration rates. The data presented in this work coupled with previously published reports involving CMNQ support the proposal for a mitochondrial level of action for this bioreductive alkylating antineoplastic agent.

Adenosine Diphosphate↗
PubMed1976

Mode of action of the bioreductive alkylating agent, 2,3-bis(chloromethyl)-1,4-naphthoquinone.

The bioreductive alkylating agent, 2,3-bis(chloromethyl)-1,4-napthoquinone (CMNQ), has been shown to inhibit the growth of Sarcoma 180 ascites cells in vivo. Evidence for the reductive activation of this agent via the mitochondrial respiratory chain was provided by CMNQ-induced oxidation of reduced nicotinamide adenine dinucleotide; the interaction was shown to be on the substrate side of the site of rotenone inhibition. Consistent with the concept that reduction of CMNQ to a hydroquinone results in the generation of an alkylating species (i.e., a quinone methide) was the finding that radioactivity from [14C]CMNQ present in Sarcoma 180 ascites cells was associated with DNA, RNA, and protein for a period of up to 72 hr after exposure to tumor-bearing animals to this agent. Inhibition of the incorporation of [3H]thymidine, [3H]uridine, and [14C]leucine into DNA, RNA, and protein, respectively, of Sarcoma 180 ascites cells was produced by this agent, with DNA biosynthesis being the most susceptible. The inhibitory effect of CMNQ on the formation of DNA was, at least in part, the result of a prevention of the conversion of thymidine to its nucleotide forms. This action was due to (a) a drug-induced decrease in intracellular levels of adenosine 5'-triphosphate, presumably resulting from uncoupling of oxidative phosphorylation by CMNQ; and (b) a partial loss of thymidine kinase activity in Sarcoma 180 cells, which did not appear to be due to direct inhibition of the enzyme by the drug. Although the primary event produced by CMNQ at the mitochondrial level appeared to be release of respiratory control, other effects of mitochondrial metabolism occurred. These included inhibition of reduced nicotinamide adenine dinucleotide and succinoxidase activities, as previously demonstrated, and mitochondrial swelling, which suggested interaction of CMNQ with the inner mitochondrial membrane. These findings indicate a variety of biochemical lesions are associated with the antineoplastic activity of CMNQ and demonstrate a relationship between the effects of this drug on mitochondrial respiratory control and DNA biosynthesis.

Adenosine Diphosphate↗