Reduction of the toxicity of “radiomimetic” alkylating agents in rats by thiol pretreatment part II. Mechanism of protection

Calcutt, G.; Connors, T. A.; Elson, L. A.; Ross, W. C. J.

doi:10.1016/0006-2952(63)90113-8

Cited by 20 publications

(4 citation statements)

References 13 publications

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“…Fig. i shows the dose response relations in the rat of the alkylating agent aminochlorambucil (Calcutt et al, 1963) growth retardation (Li) and lethality. All are responses to single doses of the compound dissolved in a propylene glycol-ethanol-HCl buffer and administered by intraperitoneal injection.…”

Section: A Elsonmentioning

confidence: 99%

“…In these cases, thiol pretreatment would appear to have an adverse effect with regard to selectivity of anti-tumour action. The degree of protection afforded by a thiol against tissue damage by alkylating agents is proportional to the intracellular concentration of thiol obtained in that tissue at the time of administration and duration of action of the the alkylating agent (Calcutt et al, 1963). The increased dose reduction factor shown by these tumours is hence explainable by the higher concentration of cysteine given as a single injection attained in the tumours relative to the concentrations attaining in the normal tissues such as bone marrow and spleen.…”

mentioning

confidence: 99%

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Growth Inhibitory and Haematological Effects of Alkylating Agents and Attempts at their Modification to give Greater Selectivity of Anti-Tumour Action

1967

Acta genet. med. gemellol.

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SummaryAttempts to induce greater relative tumour specificity in cancer chemotherapeutic drugs may be aimed at (1) reducing toxicity towards host tissues or (2) increasing the susceptibility of the tumor.1. Pretreatment with certain thiol derivatives has some protective action against the host toxicity of X-irradiation and of certain alkylating agents. However, in many cases even better protection against the tumour-inhibitory action occurs so that the therapeutic index is unfavourably affected.2. Pretreatment with glucose which accentuates the pH difference between normal and tumour tissues can, in some cases, produce an increase in therapeutic index.3. The most encouraging aspect is to explore and take advantage of biochemical variations from the normal tissue pattern which are found in certain tumours, e.g. the successful treatment of the ADJ/PC5 mouse myeloma with «aniline mustard» is believed to be related to the very high glucuronidase activity of this tumour.

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Section: A Elsonmentioning

confidence: 99%

mentioning

confidence: 99%

Growth Inhibitory and Haematological Effects of Alkylating Agents and Attempts at their Modification to give Greater Selectivity of Anti-Tumour Action

1967

Acta genet. med. gemellol.

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“…alkylating agents reside in their lack of specificity vis-&-vis the cancer cell and the development on the part of the latter of resistance, whether by adaptation or selection. So far as the basis for resistance is concerned, attention must be drawn to an interesting recent observation by Calcutt et al (1963) of a correlation between such resistance and the ratio of protein-bound to free sulphydryl groups in the same cells. About the future of these agents in chemotherapy, we do not know; in time they may be rendered obsolete by fresh develop?…”

Section: General Introductionmentioning

confidence: 99%

General Introduction

Haddow

1963

Proceedings of the Royal Society of Medicine

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“…(5). It has been reported (6,(11)(12)(13)(14) that the administration of cysteine or glutathione provides protection against the untoward effects of various aliphatic and aromatic mustards, triethylenemelamine, x-rays, and ionizing radiation. Conceivably, cysteine and glutathione may provide a natural defense against tumor producing free radicals generated within the body, as well as synthetic or naturally occurring alkylating agents which are absorbed into the body.…”

Section: Environmental Health Perspectivesmentioning

confidence: 99%

Preliminary studies on the fate of inhaled vinyl chloride monomer (VCM) in rats.

Hefner¹,

Watanabe²,

Gehring³

1975

Environ Health Perspect

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Rats were exposed to vinyl chloride monomer gas (VCM) in a closed recirculating system. The rate at which VCM was removed from the system via metabolism was determined for rats exposed to initial concentrations of VCM ranging from 50 to 1167 ppm. Upon exposure to initial concentrations of 50 to 105 ppm, the rate of metabolism was 8.04 + 3.40 X 10-8 min-1. Upon exposure to initial concentrations ranging from 220 to 1167 ppm, the rate constants were less; the mean value being 2.65 ± 1.35 X 10-8 min-'. Regardless of concentration, the disappearance followed apparent first order kinetics.Pretreatment of rats with pyrazole prior to exposure to initial concentrations of 65 and 1234 ppm VCM caused 71 and 87% reductions in the rate of metabolism. Ethanol caused 96% and 83% reductions in the rate of VCM metabolism by rats exposed to 56 and 97 ppm VCM, respectively. Ethanol was less effective in blocking the rate of metabolism by rats exposed to high concentrations of VCM; 46 and 36% in rats exposed to 1025 and 1034 ppm VCM. In rats exposed to an initial concentration of 65 ppm VCM, SKF-525-A administration caused no inhibition of the rate of VCM metabolism; however, a 19% inhibition was seen in rats exposed to 1038 ppm.The nonprotein sulfhydryl content of the liver (glutathione and cysteine) of rats exposed to VCM concentrations ranging from 50 to 15,000 ppm VCM is reduced without a relationship to dose. With repeated daily exposure the degree of reduction is reduced. Preliminary results indicate that the primary metabolites of VCM react with the nonprotein sulfhydryl. Final metabolic products excreted in the urine appear to be S-(2-hydroxyethyl)cysteine and S-(2-carboxymethyl)cysteine and the respective N-acetyl derivatives. Monochloroacetic acid was identified as another potential metabolite.Considering the results in toto, it is hypothesized that VCM is readily and extensively metabolized. Metabolism via the primary pathway, postulated to involve alcohol dehydrogenase, is swamped by exposures to concentrations exceeding 220 ppm. In rats exposed to concentrations at and exceeding this level, metabolism occurs via a secondary pathway(s), postulated to be epoxidation and/or peroxidation. These results are considered pertinent in assessing the potential hazard at low level exposures to VCM.

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Reduction of the toxicity of “radiomimetic” alkylating agents in rats by thiol pretreatment part II. Mechanism of protection

Cited by 20 publications

References 13 publications

Growth Inhibitory and Haematological Effects of Alkylating Agents and Attempts at their Modification to give Greater Selectivity of Anti-Tumour Action

Growth Inhibitory and Haematological Effects of Alkylating Agents and Attempts at their Modification to give Greater Selectivity of Anti-Tumour Action

General Introduction

Preliminary studies on the fate of inhaled vinyl chloride monomer (VCM) in rats.

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