Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: KEOCYT, Immeuble Cap Sud, 106 avenue Marx Dormoy, 92120 Montrouge, FRANCE
Pharmacotherapeutic group: Antineoplastic alkylating agent-Nitrosoureas
ATC code: L01AD04
The antineoplastic activity of streptozocin was assessed in vitro, and in vivo, using mice bearing different tumor types.
Streptozocin undergoes spontaneous decomposition to produce reactive methylcarbonium ions that alkylate DNA and cause interstrand cross-links. Severe DNA damage by streptozocin results in cell death by apoptosis or necrosis. Furthermore, the DNA strand breaks resulting from the alkylating action of streptozocin can lead to chromosomal rearrangements. In addition, cytogenetic damage by streptozocin can be manifested as chromosomal aberrations, sister chromatid exchanges or micronuclei.
In comparison with other nitrosoureas, the alkylating activity of Zanosar is weak: the methylnitrosourea metabolite has 3 to 4 times the alkylating activity of the parent compound. The presence of the glucose moiety reduces the alkylating action, but also reduces the bone marrow toxicity.
In clinical studies, Zanosar in combination with 5-fluorouracil demonstrated a benefit in the treatment of pancreatic neuroendocrine tumours, with response rates of 20 to 40%.
Three randomized clinical studies evaluated the efficacy and safety of streptozocin in pancreatic neuroendocrine tumours.
The high responses obtained in the first two trials were based on assessment of biochemical markers and clinical hepatomegaly. These high response rates have not been achieved in later studies, due more stringent efficacy criteria.
Moertel 1980: streptozocin alone vs. streptozocin + 5-FU
Moertel 1992: streptozocin + doxorubicin vs. streptozocin + 5-FU vs. chlorozotocin
Meyer 2014: streptozocin + capecitabine vs. streptozocin + capecitabine + cisplatin
Eriksson 1990: streptozocin + doxorubicin vs. streptozocin + 5-FU
Turner 2010: Streptozocin + 5-FU
After i.v. administration of radiolabeled streptozocin, the unchanged drug was cleared from the plasma within a few minutes (initial half-life: 5 minutes and terminal half-life: 35 minutes). The metabolites had a much longer half-life (>24H). These metabolites entered the central nervous system whereas there was no parent drug in the cerebrospinal fluid. Around 30% of the dose was excreted in urine as nitrosourea containing metabolites the first 24 hours after dose. Parent drug accounted for 10-20% of the renal excretion. Less than 1% of the radiolabeled dose was recovered in faeces.
In vitro data did not indicate involvement of microsomal CYP enzymes in the degradation of streptozocin. Streptozocin was not found to inhibit CYP450 enzymes in vitro.
Conventional studies with streptozocin, including short term toxicology studies, genotoxicity and reproductive toxicity studies were conducted in mice, rats, rabbits, dogs and monkeys.
Repeated dose studies in dogs and monkeys given intravenous injections of streptozocin show systemic toxicity at clinically relevant doses.
No formal carcinogenicity studies were conducted with streptozocin. In line with its pharmacological action, streptozocin is genotoxic (see section 5.1). Consequently, streptozocin may pose a carcinogenic hazard following topical exposure if not properly handled (see section 6.6).
At clinically relevant doses, streptozocin adversely affected fertility in male and female rats and induced embryo-foetal toxicity, in rats and rabbits.
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