Pharmacological and Pathological Effects of Alkylating Agents

Sternberg, Stephen S.; Philips, Frederick S.; Scholler, Jean

doi:10.1111/j.1749-6632.1958.tb42642.x

Cited by 52 publications

(11 citation statements)

References 9 publications

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“…This dose level contrasts with some reports. Dollery (1999) gave the single dose mouse IP LD 50 as 160 mg/kg, and Sternberg et al (1958) give 125 mg/kg. Alexander and Connell (1960) state that there was no mortality in mice treated IP at 60 mg/kg, but mortality was evident at 90 mg/kg.…”

Section: Discussionmentioning

confidence: 99%

Haemotoxicity of busulphan, doxorubicin, cisplatin and cyclophosphamide in the female BALB/c mouse using a brief regimen of drug administration

et al. 2010

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Many anticancer drugs are myelotoxic and cause bone marrow depression; however, generally, the marrow/blood returns to normal after treatment. Nevertheless, after the administration of some anti-neoplastic agents (e.g. busulphan, BU) under conditions as yet undefined, the marrow may begin a return towards normal, but normality may not be achieved, and late-stage/residual marrow injury may be evident. The present studies were conducted to develop a short-term mouse model (a 'screen') to identify late-stage/residual marrow injury using a brief regimen of drug administration. Female BALB/c mice were treated with BU, doxorubicin (DOX), cisplatin (CISPLAT) or cyclophosphamide (CYCLOPHOS) on days 1, 3 and 5. In 'preliminary studies', a maximum tolerated dose (MTD) for each drug was determined for use in 'main studies'. In main studies, mice were treated with vehicle (control), low and high (the MTD) dose levels of each agent. Necropsies were performed, and blood parameters and femoral/humeral nucleated marrow cell counts (FNCC/HNCC) were assessed on six occasions (from days 1 to 60/61 post-dosing). Late-stage/residual changes were apparent in BU-treated mice at day 61 post-dosing: RBC, Hb and haematocrit were reduced, mean cell volume/mean cell haemoglobin were increased and platelet and FNCC counts were decreased. Mice given DOX, CISPLAT and CYCLOPHOS, in general, showed no clear late-stage/residual effects (day 60/61). It was concluded that a brief regimen of drug administration, at an MTD, with assessment at day 60/61 post-dosing was a suitable short-term method/screen in the mouse for detecting late-stage/residual marrow injury for BU, a drug shown to exhibit these effects in man.

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Section: Discussionmentioning

confidence: 99%

Haemotoxicity of busulphan, doxorubicin, cisplatin and cyclophosphamide in the female BALB/c mouse using a brief regimen of drug administration

et al. 2010

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“…Cyclophosphamide has been found to cause many toxic effects 3 These include haemorrhagic cystitis, pulmonary fibrosis, irreversible azospermia in man, gastrointestinal bleeding etc. 2 Toxic effects also include micro vascular fatty changes in liver.…”

Section: Introductionmentioning

confidence: 99%

Effect of cyclophosphamide on the microanatomy of liver of albino rats

et al. 2014

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“…Reserpine reduced the toxicity of nitromin probably on the central nervous system. With nitrogen mustard which has a weaker action than nitromin on the central nervous system, the inhibitory effect of reserpine on the lethality was not so remarkable, but with myleran which has a comparatively strong central action (24), inhibitory effect of reserpine on lethality of myleran was predominant.…”

Section: Discussionmentioning

confidence: 95%

Action of Reserpine on the Lethal Effect of Cytotoxic Alkylating Agents

Yamamoto

Kimura

Iwatsubo

1968

Japanese Journal of Pharmacology

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Since 1953 we have studied the specific toxicogenic mechanism of various nitrogen mustard derivatives (1-10). As described by Philips (11) , Goodman and Gilman (12) and Yamamoto et al. (4,6), the toxicity of nitrogen mustards can be broadly classified into acute and delayed cytotoxic actions , both of which are extremely specific. Because of the toxicity of these drugs there is consequently a clinical restriction in the dosage. How ever, as these nitrogen mustard derivatives show a significant morphological effect on experimental cancer, extensive basic and clinical studies are still being continued on these compounds to search more excellent cancer chemotherapy.In the present study methyl-bis (Q-chloroethyl) amine N-oxide hydrochloride (nitro min) was selected and investigations were directed to reduce its toxicity . Data obtained demonstrated that the pretreatment with reserpine inhibited the lethality of nitromin and thus further studies were made on its inhibition mechanism with relation to biogenic amines. MATERIALS AND METHODSAnimals used : In the study on effect of various drugs on the lethality of anticancer drugs and on the quantitative analysis of serotonin in tissues, male dd-strain mice weighing about 15 g were used, while Donryu rats weighing about 100 g were employed in the study on effect on the therapeutic action on Yoshida sarcoma.Compounds used: Anticancer drugs used were nitrogen mustard (methyl-bis(Q-chloro ethyl) amine hydrochloride, Yoshitomi), nitromin (methyl-bis(Q-chloroethyl) amine N oxide hydrochloride, Yoshitomi), myleran (1, 4-di (methanesulfonyloxy) butane , Takeda). Chlorpromazine, reserpine, tetrabenazine, serotonin, 5-hydroxytryptophan (5-HTP) , DL-3, 4-dihydroxyphenylalanine (DOPA) and iproniazid were also obtained commercial ly. Myleran, 5-HTP and DOPA were used as 1 per cent CMC aqueous suspension and the other drugs were diluted in distilled water, and injected all intraperitoneally .Determination of LD50: Mice were used in a group of more than 10 . According to the description of Yamamoto et al. (1), LD50 was determined 10 days after the administ ration of the anticancer drugs by the calculation method of Litchfield and Wilcoxon (13) .Evaluation of effect of nitromin on Yoshida sarcoma : Four to 6 days after intraperitoneal transplantation of Yoshida sarcoma to rats , ascites was obtained and 0.1 ml of the ascites

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Pharmacological and Pathological Effects of Alkylating Agents

Cited by 52 publications

References 9 publications

Haemotoxicity of busulphan, doxorubicin, cisplatin and cyclophosphamide in the female BALB/c mouse using a brief regimen of drug administration

Haemotoxicity of busulphan, doxorubicin, cisplatin and cyclophosphamide in the female BALB/c mouse using a brief regimen of drug administration

Effect of cyclophosphamide on the microanatomy of liver of albino rats

Action of Reserpine on the Lethal Effect of Cytotoxic Alkylating Agents

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