Modification by WR 2721 of the response to chemotherapy of tumours and normal tissues in the mouse

Twentyman, Peter R.

doi:10.1038/bjc.1983.7

Cited by 22 publications

(5 citation statements)

References 9 publications

(10 reference statements)

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“…Several potential renoprotective agents (e.g., amifostine and antioxidants) have been examined for preventing and/or treating cisplatin-AKI (52,84). However, their success has been limited by their ineffectiveness, adverse side effects, costs, and potential to limit cisplatin's anti-tumor efficacy (71,72,74,84). For example, amifostine, which protects the kidneys by detoxifying platinum-DNA adducts and binding to and neutralizing free radicals, is the only FDAapproved agent for reducing cisplatin-associated nephrotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…For example, amifostine, which protects the kidneys by detoxifying platinum-DNA adducts and binding to and neutralizing free radicals, is the only FDAapproved agent for reducing cisplatin-associated nephrotoxicity. Yet its use is constrained by its side effects and cost (70) as well as its potential to limit cisplatin's anti-tumor efficacy by reducing platinum-DNA adducts (71,72,74). Thus, the risk of irreversible renal injury persists among patients receiving cisplatin, supporting the need to explore additional strategies for protecting against cisplatin-mediated nephrotoxicity without compromising its ability to kill tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous approaches for protecting against cisplatin-mediated nephrotoxicity have been investigated. However, they have failed to reproducibly and successfully protect the kidneys without injurious side effects, and many therapies examined were reported to compromise cisplatin's anti-neoplastic effects (71,72,74). In this study, we extended our previous findings using immunocompromised human tumor-bearing mice and investigated the effect of Mg deficiency (ϮMg supplementation) on cisplatin-induced AKI and cisplatin-mediated tumor killing using the CT26 colon cancer model in immunocompetent BALB/c mice.…”

mentioning

confidence: 89%

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Magnesium improves cisplatin-mediated tumor killing while protecting against cisplatin-induced nephrotoxicity

Kumar

Solanki

Xue

et al. 2017

American Journal of Physiology-Renal Physiology

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Approximately 30% of all cancer patients treated with cisplatin, a widely used broad-spectrum chemotherapeutic agent, experience acute kidney injury (AKI). Almost all patients receiving cisplatin have magnesium (Mg) losses, which are proposed to aggravate AKI. Currently, there are no methods to successfully treat or prevent cisplatin-AKI. Whereas Mg supplementation has been shown to reduce AKI in experimental models and several small clinical trials, the effects of Mg status on tumor outcomes in immunocompetent tumor-bearing mice and humans have not been investigated. The purpose of this study was to further examine the effects of Mg deficiency (±Mg supplementation) on cisplatin-mediated AKI and tumor killing in immunocompetent mice bearing CT26 colon tumors. Using a model where cisplatin alone (20 mg/kg cumulative dose) produced minimal kidney injury, Mg deficiency significantly worsened cisplatin-mediated AKI, as determined by biochemical markers (blood urea nitrogen and plasma creatinine) and histological renal changes, as well as markers of renal oxidative stress, inflammation, and apoptosis. By contrast, Mg supplementation blocked cisplatin-induced kidney injury. Using LLC-PK renal epithelial cells, we observed that Mg deficiency or inhibition of Mg uptake significantly enhanced cisplatin-induced cytotoxicity, whereas Mg supplementation protected against cytotoxicity. However, neither Mg deficiency nor inhibition of Mg uptake impaired cisplatin-mediated killing of CT26 tumor cells in vitro. Mg deficiency was associated with significantly larger CT26 tumors in BALB/c mice when compared with normal-fed control mice, and Mg deficiency significantly reduced cisplatin-mediated tumor killing in vivo. Finally, Mg supplementation did not compromise cisplatin's anti-tumor efficacy in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 89%

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Magnesium improves cisplatin-mediated tumor killing while protecting against cisplatin-induced nephrotoxicity

Kumar

Solanki

Xue

et al. 2017

American Journal of Physiology-Renal Physiology

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“…P 388 leukemia and Lewis lung carcinoma were protected against radiation (2). KHT and RIF-I sarcomas were protected against cyclophosphamide (14). SA FA (a moderately differentiated fibrosarcoma) and CA MT (an anaplastic tumor) were protected against radiation (13).…”

Section: Discussionmentioning

confidence: 98%

Effect of the Radioprotector WR 2721 on the Response of Metastatic Lewis Lung Carcinoma Colonies to Alkylating Agents

Wist¹

1985

Acta Radiologica: Oncology

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“…The extreme hypothermic conditions induced by 3 x 200 mg kg-' amifostine, however, did result in a less pronounced potentiation of the efficacy of carboplatin. Because hypothermia is related to the dose of amifostine, it also explains the suggested tumour protection by the compound when given as a single dose of 400 mg kg-' (Twentyman, 1983). From other studies in which reduction in body temperature by amifostine has been described in Balb/c ( Van der Wilt et al, 1992) and severe combined immunodeficient (SCID) mice (Paine et al, 1996), it appears that the extent of this side-effect varies between different strains of mice.…”

Section: Anti-tumour Activitymentioning

confidence: 99%

Influence of single and multiple doses of amifostine on the efficacy and the pharmacokinetics of carboplatin in mice

Korst

Boven²,

Sterre³

et al. 1997

Br J Cancer

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Summary We have previously reported that amifostine potentiates the anti-tumour activity of carboplatin in mice. The present study was carried out in well-established human ovarian cancer xenografts OVCAR-3, A2780 and FMa grown subcutaneously in the nude mouse. It was found that a single dose of amifostine resulted in a higher increase in the anti-tumour activity of carboplatin than three doses of amifostine. A single dose of amifostine increased the AUC (area under the curve) values of total platinum in plasma ultrafiltrate (30.1 vs 18.2 gM X h), liver (307.7 vs 236.4 nmol g-1 x h), kidney (500.8 vs 368.3 nmol g-' x h) and OVCAR-3 tumour tissue (184.0 vs 146.8 nmol g-' x h). Despite this increase in total platinum, a decrease in platinum (Pt)-DNA adduct levels was observed in liver, kidney and bone marrow, which was significant in liver. In tumour tissue an insignificant increase in Pt-DNA adduct levels, specifically the Pt-GG adduct, was observed after treatment with a single dose of amifostine, which may explain the increase in anti-tumour activity. The increase in the AUC of total platinum was probably caused by a reduction in body temperature, which was most severe after three doses of amifostine. The extreme hypothermia may be the reason that three doses of amifostine resulted in less potentiation of the efficacy of carboplatin.Keywords: amifostine; carboplatin; pharmacokinetics; anti-tumour activity; platinum-DNA adduct; hypothermia Carboplatin [cis-diammine( 1,1 -cyclobutanedicarboxylato)platinum(II)] was developed as a second-generation platinum compound with less nephrotoxicity than cisplatin. Its anti-tumour activity is assumed to result from the formation of platinum (Pt)-DNA adducts. The clinical use of carboplatin is limited by myelosuppression at a dose in the steep part of the dose-response curve. Therefore, much effort has been put into reducing the toxic side-effects to allow the administration of higher doses of carboplatin.Amifostine [Ethyol, WR-2721, S-2-(3-aminopropylamino)-ethylphosphorothioic acid], initially developed as a radioprotector, is approved for use as a protector against chemotherapy-induced toxicities in the USA and Europe (van der Vijgh and Peters, 1994). A selective protection against the side-effects of platinum compounds has been observed in clinical and preclinical studies (Treskes et al, 1992a(Treskes et al, , 1994 Capizzi, 1994;van der Vijgh and Peters, 1994). Amifostine is the prodrug of the aminothiol compound WR-1065 (Figure 1), which inhibits DNA platination (Treskes et al, 1992b). The selective protection is based on the preferential formation and uptake of this active metabolite in nontumour tissues (Yuhas, 1980;Brown et al, 1988;Calabro-Jones et al, 1988;Shaw et al, 1988).In vitro experiments have shown that the modifying action of amifostine was protection rather than rescue from toxicity (Treskes et al, 1992b (Utley et al, 1984;Shaw et al, 1988Shaw et al, , 1994, optimal protection would be achieved when amifostine is administered shortly before the platinu...

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Modification by WR 2721 of the response to chemotherapy of tumours and normal tissues in the mouse

Cited by 22 publications

References 9 publications

Magnesium improves cisplatin-mediated tumor killing while protecting against cisplatin-induced nephrotoxicity

Magnesium improves cisplatin-mediated tumor killing while protecting against cisplatin-induced nephrotoxicity

Effect of the Radioprotector WR 2721 on the Response of Metastatic Lewis Lung Carcinoma Colonies to Alkylating Agents

Influence of single and multiple doses of amifostine on the efficacy and the pharmacokinetics of carboplatin in mice

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