Clinical antitumor activity and toxicity of streptozotocin (NSC-85998)

Alloxan and streptozotocin are toxic glucose analogues that preferentially accumulate in pancreatic beta cells via the GLUT2 glucose transporter. In the presence of intracellular thiols, especially glutathione, alloxan generates reactive oxygen species (ROS) in a cyclic redox reaction with its reduction product, dialuric acid. Autoxidation of dialuric acid generates superoxide radicals, hydrogen peroxide and, in a final iron-catalysed reaction step, hydroxyl radicals. These hydroxyl radicals are ultimately responsible for the death of the beta cells, which have a particularly low antioxidative defence capacity, and the ensuing state of insulin-dependent 'alloxan diabetes'. As a thiol reagent, alloxan also selectively inhibits glucose-induced insulin secretion through its ability to inhibit the beta cell glucose sensor glucokinase. Following its uptake into the beta cells, streptozotocin is split into its glucose and methylnitrosourea moiety. Owing to its alkylating properties, the latter modifies biological macromolecules, fragments DNA and destroys the beta cells, causing a state of insulin-dependent diabetes. The targeting of mitochondrial DNA, thereby impairing the signalling function of beta cell mitochondrial metabolism, also explains how streptozotocin is able to inhibit glucose-induced insulin secretion.

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“…Streptozotocin is an antimicrobial agent and has also been used as a chemotherapeutic alkylating agent [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

The mechanisms of alloxan- and streptozotocin-induced diabetes

2007

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“…Streptozotocin is an antibiotic isolated from Streptomyces achromogenes (Herr et al, 1960) and is a diabetogenic compound with a direct toxic action on pancreatic f cells (Rakieten, Rakieten and Nadkarni, 1963;Jurod et al, 1967;Karunanayake et al, 1967). This toxic action has been utilized therapeutically in man in the treatment of islet-cell tumours (Editorial, 1975;Murray-Lyon et al, 1968;Gagel et al, 1976) and other malignancies (Schein et al, 1974;Du Priest et al, 1975). Streptozotocin induces epithelial tumours in the rat kidney (Arison and Feudale, 1967;Rakieten et al, 1968;Mauer et al, 1974a) butt sarcomas do not appear to have been reported.…”

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confidence: 99%

Streptozotocin-induced renal tumours in rats

Horton¹,

Fox²,

Corrin³

et al. 1977

Br J Cancer

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Summary.-Forty-six separate renal tumours developed in 36/80 Wistar male rats given a single i.v. dose of streptozotocin (25 mg/kg body wt) to induce diabetes mellitus. Fourteen of the tumours were epithelial in type, 8 were wholly mesenchymal and 24 were largely mesenchymal but also contained epithelial elements. The purely epithelial tumours correspond to the renal adenomas and adenocarcinomas seen in man. The mesenchymal tumours were composed either of undifferentiated spindle cells or of a mixture of poorly differentiated mesenchyme and epithelial glands. Microscopically, the mixed tumours resembled the nephroblastomas seen in man; both elements appeared to be malignant, but in the absence of metastases this remains unproven. The management of the diabetic state did not influence the incidence of tumours, but insulin appeared to enhance tumour growth.

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“…Control animals in these studies are usually injected with citrate buffer solution. However, STZ is known to possess pharmacological effects other than its diabetogenic properties (Schein et al, 1974), and extra pancreatic actions of streptozotocin cannot be excluded. The presence of GLUT2 in liver and kidney might explain the long-term complications seen with hepatic and renal tumors in rats treated with streptozotocin (Delahunt et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Anti hyperglycemic activities of <i>Annona muricata</i> (Linn)

Adeyemi¹,

Komolafe²,

Adewole³

et al. 2010

Afr. J. Trad. Compl. Alt. Med.

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This study was designed to determine the effects of methanolic extracts of Annona muricata (Linn) on the blood glucose level of streptozotocin-induced diabetic Wistar rats. Thirty adult Wistar rats were randomly assigned into three groups (A, B and C) of ten rats each. Group A was the control, Group B was untreated hyperglycemic group and group C was A. muricata-treated group. Hyperglycemia was induced in groups B and C by a single intraperitoneal injection of 80mg/kg streptozotocin dissolved in 0.1M citrate buffer. The control group was intraperitoneally injected with equivalent volume of citrate buffer and all the animals were monitored for four weeks. Daily intra peritoneal injection of 100mg/kg A. muricata was administered to group C rats for two weeks and the animals were monitored for another two weeks. The data obtained were analyzed with descriptive and inferential statistics. The result showed a mean body weight of 206 + 7.74g, 173.29+5.13g and 197 + 5.62g respectively for the control, untreated diabetic and A. muricata-treated diabetic group, and a mean blood glucose concentration of 3.78 + 0.190 mmol/L, 21.64 + 2.229mmol/L and 4.22 + 0.151mmol/L for the control, untreated diabetic and treated diabetic groups respectively. A significant difference exists between the blood glucose concentrations of treated and untreated hyperglycemic groups of rats. The result of this study demonstrated that A. muricata possesses anti-hyperglycemic activities.

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Clinical antitumor activity and toxicity of streptozotocin (NSC-85998)

Cited by 182 publications

References 8 publications

The mechanisms of alloxan- and streptozotocin-induced diabetes

The mechanisms of alloxan- and streptozotocin-induced diabetes

Streptozotocin-induced renal tumours in rats

Anti hyperglycemic activities of <i>Annona muricata</i> (Linn)

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