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Biomedical subjects

M Rabinovitz

Publications and source records attributed to M Rabinovitz.

At least 73 records · Page 4Linked to original sources
PubMed1985

Depletion of extracellular cysteine with hydroxocobalamin and ascorbate in experimental murine cancer chemotherapy.

Treatment of mice bearing P388 lymphocytic leukemia with combined hydroxocobalamin (0.1 mmol/kg) and sodium ascorbate (1.0 mmol/kg) for 10 consecutive days resulted in 70% increase in survival. Treatment with dehydroascorbate (1.0 mmol/kg) similarly increased survival. The extended treatment for 15 days posttumor inoculation failed to improve survival as did lowering the tumor inocula from 10(6) to 10(4) cells in similarly treated mice. P388 cells in primary culture with cystine as a source of cysteine require exogenous thiols or disulfides for growth and also grow with cysteine but only when trace copper is sequestered with bathocuproine sulfonate. This is due to the copper catalyzed oxidation of cysteine to cystine, which these cells cannot utilize. Cells grew in medium preincubated for 8 h with cysteine and bathocuproine sulfonate, but lysed when the preincubated medium included hydroxocobalamin (10 microM) and sodium ascorbate (100 microM). This defect was corrected by resupplementation with cysteine or cystine plus bishydroxyethyl disulfide after addition of the cells. Further support for cysteine depletion as a factor in therapy is obtained by therapeutic interference with 4-thiamethionine (25 mumol/kg). This mixed disulfide of cysteine and methyl mercaptan enters cells as a methionine analogue, is reduced to supply cysteine, and thus withstands the oxidative environment that limits the utilization of cysteine as a nutrient. These results suggest that dehydroascorbate is generated from combined hydroxocobalamin and ascorbate and accounts for the thiol-prive activity of combined hydroxocobalamin and ascorbate therapy. The ultimate failure of therapy by thiol oxidation may be due to the increased availability of cysteine produced by host tissues, possibly infiltrating macrophages, that occurs independently of extended treatment and the size of the tumor inoculum.

Animals↗
PubMed1985

Methylthio-capping of selenocysteamine: preliminary studies on selective toxicity for cancer chemotherapy.

Dimethyl disulfide markedly increased the cytotoxicity of selenocystamine by 2 orders of magnitude, from 40 microM to 0.5 microM for 50% inhibition of growth in 45 hr. When mice were injected ip with 22 microMole/Kg of selenocystamine on Day 0, all were dead on Day 4. If dimethyl disulfide (500 microMole/Kg) was either mixed with the selenocystamine or injected immediately prior to it, the mice survived treatment for at least 21 days afterwards, suggesting that methylthio-capping of selenocysteamine reduced host toxicity. Such combined treatment may be of value in chemotherapy.

Animals↗
PubMed1984

[Captopril].

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Captopril↗
PubMed1984

Protection of murine L1210 leukemia and bone marrow progenitor cells against mechlorethamine and inhibition of choline uptake as a structure-activity relationship of 2-dimethylaminoethanol and its analogues.

The structure-activity relationships of 2-dimethylaminoethanol and its analogues as protectors against mechlorethamine cytotoxicity and as inhibitors of choline uptake were evaluated. Of a series of inhibitors and protectors, 2-dimethylaminoethanol was the most potent inhibitor of choline uptake and the most potent protector of both hematopoietic progenitor cells and murine L1210 leukemia cells. Two analogues that exhibited both potent protection and inhibition were 1-dimethylamino-2-propanol and 2-ethylmethylaminoethanol. 2-Di-n-butylaminoethanol, while protecting against mechlorethamine cytotoxicity, was not an inhibitor of choline uptake. 2-n-Butylmethylaminoethanol, while an inhibitor of choline uptake, was not a protector against mechlorethamine cytotoxicity. Addition of 2-dimethylaminoethanol to mechlorethamine in a mole ratio of 1000:1 did not improve survival of tumor-bearing mice beyond that of mice treated with mechlorethamine alone.

Animals↗
PubMed1983

Evidence for a membrane sulfhydryl associated with resistance to melphalan in a murine L1210 leukemia line.

Murine L1210 leukemia cells, which display sensitivity or resistance to the chemotherapeutic alkylating agent, melphalan, are equivalently sensitive or resistant to the poorly permeable mercurial, p-chloromercuribenzenesulfonate. Cells of both lines do not differ in sensitivity to the sulfhydryl reagents, N-ethylamaleimide, iodoacetamide and iodoacetate or to the glutathione transferase substrates 1-chloro-2,4-dinitrobenzene and p-nitrobenzyl chloride. The results are interpreted in terms of the known biological reactivity of p-chloromercuribenzenesulfonate as a selective reagent for sulfhydryl groups of membrane proteins associated with monovalent cation permeability.

Animals↗
PubMed1983

2,9-Dimethyl-1,10-phenanthroline (neocuproine): a potent, copper-dependent cytotoxin with anti-tumor activity.

2,9-Dimethyl-1,10-phenanthroline (2,9-DMP), a copper-specific chelator, was a potent cytotoxin against L1210 cells in vitro; its activity was dependent upon available Cu2+ in the medium. Other divalent ions, Fe2+ and Zn2+, were ineffective as promoters of growth inhibition. As the copper chelate, a 4 microM solution produced a 4 log kill after a 1-hr incubation. This was in marked contrast to 1,10-phenanthroline, whose inhibition of cell growth was overcome by added Cu2+, Fe2+ and Zn2+. Cellular uptake of labeled 2,9-dimethyl-1,10-phenanthroline also required added Cu2+ in the medium. This transport was energy dependent, and the drug was concentrated over 200-fold by the cells. In preliminary evaluations, copper-2,9-DMP showed significant chemotherapeutic activity against the P388 murine lymphoma in vivo.

Animals↗
PubMed1983

Fluorine substitution as a probe for the role of the 6-position of benzo[a]pyrene in carcinogenesis.

The tumorigenic activities of benzo[a]pyrene (BP) and 6-fluorobenzo[a]pyrene (6-F-BP) were compared to determine whether an unsubstituted 6-position is important for the carcinogenic effect of BP. Highly purified samples of 6-F-BP and BP had similar activities for the induction of lung adenomas in Swiss Webster mice treated before weaning. The 6-fluoro derivative, however, had about one-half as much activity as BP for the initiation of skin papillomas in CD-1 mice. Similarly, 6-F-BP (approximately equal to 90% purity) had about one-half the activity of BP for the induction of skin tumors in C57BL/6J mice given repetitive treatments of the hydrocarbons and for the induction of sarcomas in C3H/fCum mice given a single sc injection. 6-F-BP (approximately equal to 90% purity) had activity similar to that of BP for induction of sarcomas at the sc injection site in Fischer 344 rats. These results and related data indicate the need for detailed metabolic studies whenever fluorine substitution is used as a probe to assess the role of the unsubstituted position in the carcinogenicity of the parent compound.

Animals↗
PubMed1982

Tetraalkylammonium ions: protection of murine L1210 leukemia and bone marrow progenitor cells in vitro against mechlorethamine cytotoxicity and inhibition of the choline transport system.

In the series of tetraalkylammonium ions from tetramethylammonium to tetra-n-heptylammonium, tetra-n-pentylammonium ion was a potent protector of both murine L1210 leukemia and bone marrow progenitor cells against mechlorethamine cytotoxicity. It was also a non-competitive inhibitor of choline uptake. Phosphonium analogs of the tetraalkylammonium ions were equal to their corresponding tetraalkylammonium ions in their protection against mechlorethamine cytotoxicity and in their inhibition of choline uptake. Treatment of tumor bearing L1210 leukemia mice with the combination of tetra-n-pentylammonium ion and mechlorethamine resulted in no major improvement in survival of the tumor-bearing mice compared to mechlorethamine treatment alone.

Animals↗
PubMed1982

Ethambutol-induced thrombocytopenia.

Extreme thrombocytopenia, purpura, and melena developed in a 71-year-old woman four days after ethambutol administration was started. The macrophage inhibition factor test was positive for ethambutol, and the thrombocytopenia subsided shortly after discontinuation of the drug therapy. The sequence of events in this patient suggests that, although previously unreported, thrombocytopenia should be added to the list of side effects of ethambutol.

Aged↗
PubMed1981

Showdomycin analogues: synthesis and antitumor evaluation.

The synthesis of N-beta-D-ribofuranosyl derivatives of maleimide, 3-methylmaleimide, and 3-chloromaleimide was accomplished in three steps from ribosylamine. The synthetic ribosides can be considered N-nucleoside analogues of showdomycin, which is an antitumor antibiotic of the C-nucleoside type. Although the three analogues were cytotoxic to cultured L1210 cells, no in vivo antitumor activity was found with the murine P388 leukemia test system. Drug transport studies were done in an attempt to trace the biological fate of the analogues.

Animals↗
PubMed1981

Ethanol mustard cytotoxicity in vitro toward murine leukemia and bone marrow progenitor cells.

Ethanol mustard, 2-[bis(2-chloroethyl)amino]ethanol-picrate, was approximately one tenth as cytotoxic as mechlorethamine toward both murine bone marrow progenitor cells and L1210 leukemia cells. Choline protected cells against nitrogen mustard cytotoxicity, but increased their sensitivity toward ethanol mustard. 2-(di-n--butylamino)ethanol was the best protector of both bone marrow precursor cells and L1210 cells against ethanol mustard cytotoxicity. Both ethanol mustard and 2-(di-n-butylamino)ethanol showed non-competitive inhibition of choline transport.

Animals↗