Management of adverse side-effects after chemotherapy in macaques as exemplified by streptozotocin: case studies and recommendations

Abstract

The chemotherapeutic streptozotocin is used for induction of diabetes in animal models including non-human primates. Being a cytotoxic nitrosourea compound, it can be associated with adverse events (AEs), mainly nausea and emesis, nephrotoxicity, elevated liver transaminase levels, pulmonary oedema and, most prominently, metabolic acidosis: these can be severe in some cases. The incidence and gravity are to some extent related to the characteristics of the individual animal, diagnostic tools, prompt recognition of symptoms and supportive measures. Careful animal selection, dose adaptation and supportive actions such as renal protective hydration are the main tools in managing AEs, but do not fully eliminate unavoidable and sometimes life-threatening conditions. In our centre we have built experience in a cohort of 78 cynomolgus and rhesus macaques in which six cases manifested severe AEs (8%). This experience has prompted implementation of strategies for early detection and management of adverse effects, together with an animal refinement programme. We present here specific pretreatment regimens, post-infusion laboratory evaluations, and flow charts to assess/treat metabolic acidosis and precipitating factors. Case reports of the six animals with severe AEs are presented to illustrate management of AEs, especially metabolic acidosis, and criteria for early euthanasia where appropriate. We conclude that improved monitoring and validated tools allow for optimal management of adverse effects in an early stage of their manifestation. Reduced morbidity and mortality not only improve individual animal wellbeing but also avoid model-induced confounding that diminishes the translational value of the experimental protocol.

Streptozotocin-associated lymphopenia in cynomolgus monkeys

“…9 Histological evaluations of organs have demonstrated renal tubular necrosis and hepatic steatosis. 7,10,11 Other reported toxicities include nausea, emesis, weight loss, interrupted growth, hormone imbalance, lipid metabolism derangements, metabolic acidosis, and pulmonary edema. 11,12 In rodents, STZ has been reported to affect the immune system, being associated with bone marrow suppression, derangements in leukocyte count (leukopenia), and lymphocyte depletion in the blood and spleen, the mechanisms of which are not completely understood.…”

“…7,10,11 Other reported toxicities include nausea, emesis, weight loss, interrupted growth, hormone imbalance, lipid metabolism derangements, metabolic acidosis, and pulmonary edema. 11,12 In rodents, STZ has been reported to affect the immune system, being associated with bone marrow suppression, derangements in leukocyte count (leukopenia), and lymphocyte depletion in the blood and spleen, the mechanisms of which are not completely understood. [13][14][15][16] Direct and irreversible damage to the bone marrow and the early precursors of T cells is seen in STZ-treated mice.…”

Validity of animal models of type 1 diabetes, and strategies to enhance their utility in translational research

“…Induction protocols are designed so to eliminate endogenous insulin secretion by destroying β-cells, so that efficacy of the intended therapy can be evaluated from a 'zero' baseline in which there is only exogenous insulin supply. Chemical induction has the advantage that it can be used with various strains of rodents and also large animals: however, STZ protocols using the effective single high-dose have potential for renal-and hepato-toxicity (Carney et al, 1979;Deeds et al, 2011;Graham et al, 2011bGraham et al, , 2011cGraham et al, , 2012aInoue et al, 1994;Junod et al, 1969;Kiesel and Kolb, 1982;Koulmanda et al, 2003;Leiter, 1982;Lenzen, 2008;Palm et al, 2004;Rood et al, 2006;Shibata et al, 2002;Wei et al, 2011;Wu et al, 2009). Multiple lowdose infusions have been used in small and large animals to provoke an immune response against islets in an attempt to more closely mimic the autoimmune process in patients (KantwerkFunke et al, 1991;Rossini et al, 1977;Wei et al, 2011).…”

“…Successful management relies on frequent evaluation of a complete clinical pathology assessment and quick intervention including intensive nutrition, fluid management, insulin, and supportive care: it is strongly recommended to have proper protocols in place (Graham et al, 2012a). In the case of the NHP, vascular access ports are recommended to enable frequent blood sampling and intensive fluid management protocols in the familiar homecage, to avoid additional stressors and separation from the social cohort (Graham et al, 2009(Graham et al, , 2010.…”

The usefulness and limitations of the diabetic macaque model in evaluating long‐term porcine islet xenograft survival

“…This is illustrated by the reports of the Emory group, in which pancreatectomy in early reports [9–11] was replaced by STZ induction in more recent reports [12,16] (Table 1). Being a nitrosourea chemotoxic agent, STZ has AE in particular regarding the liver and kidney [19]. Hence, in combination with medication that has hepatotoxicity or nephrotoxicity, there is the possibility of synergism in causing AE [26].…”