The effects of co-administration of selenium and cis-platin (CDDP) on CDDP-induced toxicity and antitumour activity

Abstract

Summary The therapeutic antitumour activity and host toxicity of cis-platin (CDDP), which was administered with selenium (sodium selenite) was studied on the growth of a human yolk sac tumour grown in nude mice. Treatment consisted of CDDP single agent chemotherapy (3 weeks) or preliminary PVB combination chemotherapy (CDDP+vinblastine +bleomycin, 2 weeks). Selenium was co-administered from day 1 to 5 with each therapeutic regimen. The administration of CDDP alone caused significant reduction in tumour burden but at higher doses there was significant host toxicity. The co-administration of selenium together with CDDP (CDDP: selenium, molar ratio=3.5:1) did not affect the anti-tumour activity of CDDP but it did cause a decrease of parameters of host toxicity including lethality, increasing the 50% lethal dose (LD50) from 9.3mg kg-1 to 17.5mg kg -1. The parameters of host toxicity which were altered by selenium co-administration were nephrotoxicity, myeloid suppression and weight loss. Our study suggested that selenium coadministration allows higher doses of CDDP with reduction of apparent toxicity, resulting in a higher therapeutic index and possibly indicating a potential increase in the utilization of CDDP in clinical cancer chemotherapy.

Selective Modulation of the Therapeutic Efficacy of Anticancer Drugs by Selenium Containing Compounds against Human Tumor Xenografts

“…Selenium (sodium selenite) can reduce cisplatin-induced toxicity without reducing the antitumor activity in mice bearing yolk sac and Prima breast tumors (36,37). Data from our laboratory demonstrate that MSC potentiate cell growth inhibition induced by SN-38, and the potentiation is associated with activation of GADD153, dephosphorylation of Akt, PARP cleavage, and induction of apoptosis.…”

Chemopreventive effect of bilberry (Vaccinium myrtillus) against cisplatin-induced oxidative stress and DNA damage as shown by the comet assay in peripheral blood of rats

“…These highly reactive oxygen species can cause extensive tissue damage through reactions with all biological macromolecule, e.g., lipids, proteins and nucleic acids, leading to formation of oxidized substances, such as MDA, which is the product membrane lipid peroxidation (Halliwell & Gutteridge 1993). In animals, renal and chromosomal damage due to cisplatin, other heavy metals and doxorubicin-induced cardiomyopathy can be prevented by supplementation with high doses of antioxidants, such as selenium, vitamins C and E, without compromising the anti-tumour activity (Wang et al 1980;Fujita et al 1982;Ohkawa et al 1988;Chorvatovicova et al 1991;Whanger 1992;Jotti et al 1993). For instance, Ohkawa et al (1988) have demonstrated in mice that selenium co-administration allows higher doses of cisplatin with reduction of nephro-and hematological toxicity, resulting in a higher therapeutic index.…”

“…In animals, renal and chromosomal damage due to cisplatin, other heavy metals and doxorubicin-induced cardiomyopathy can be prevented by supplementation with high doses of antioxidants, such as selenium, vitamins C and E, without compromising the anti-tumour activity (Wang et al 1980;Fujita et al 1982;Ohkawa et al 1988;Chorvatovicova et al 1991;Whanger 1992;Jotti et al 1993). For instance, Ohkawa et al (1988) have demonstrated in mice that selenium co-administration allows higher doses of cisplatin with reduction of nephro-and hematological toxicity, resulting in a higher therapeutic index. Therefore, nutritional status of cancer patients, especially the nutritional intake of antioxidants and their concentrations in plasma and tissues may determine the extent of oxidative organ damage by free radicals produced by cytostatic drugs (Clemens et al 1990;Hay et al 1991;Forni & Armand 1994;Meyer & Madias 1994;Anderson et al 1995;Weijl et al 1997).…”

Optimising Selenium for Modulation of Cancer Treatments

“…Table II summarises extensive preclinical work that demonstrated the protective effects of various Se compounds against the toxicities of radiation (12, 36) and organ-specific toxicities of many cytotoxic drugs, including myelosuppression, mucositis, diarrhoea, alopecia, cystitis and nephrotoxicity (11, 13, 30, 37). Specific toxicities of cisplatin in kidneys, bone marrow and intestine were improved without affecting antitumour efficacy (30,(38)(39)(40)(41) or pharmacokinetics (42). Impressive protection from lethal effects of six cytotoxic drugs with 200 μg/day MSC was demonstrated in nude mice (13).…”