Sorensen, James (2020) Therapeutic Efficacy of a Co-Q10 Analogue in Combating Cachexia and Mortality Induced by Gold-Standard Paediatric Chemotherapy Regimens. PhD thesis, Victoria University.

Abstract

Chemotherapy is an effective first-line treatment against cancer; however, it induces a myriad of serious sequalae, including skeletal muscle dysfunction and wasting (SMDW) and fatigue, which we hypothesise is underpinned by mitochondrial dysfunction. When chemotherapy-induced (CI) SMDW is instigated in childhood, it often endures and manifests over the lifespan resulting in exacerbated morbidity and, in some cases, mortality. Despite much research having investigated individual chemotherapeutic agents and their effect on the skeletal muscle in mice (including our own), these models failed to evaluate the potential interactions between agents in a poly-pharmaceutical regimen, or, the effects of long-term and multi-staged chemotherapy regimens like that used in hospitals world-wide. Therefore, this thesis investigated the impact that gold-standard chemotherapy regimens used to combat the three common childhood cancers: acute lymphoblastic leukaemia (ALL), non- Hodgkin’s Burkitt lymphoma (NHBL) and medulloblastoma, on the skeletal muscle system in healthy juvenile mice and monitored the effects of treatment endured over the lifespan. After establishing pre-clinical animal models for three gold-standard chemotherapy regimens, we showed that, regardless of regimen, eight weeks of treatment to four-week-old mice induced considerable skeletal muscle dysfunction which was characterised by significant muscle weakness, fatigability and, in 2 of the 3 regimens, lean mass loss. Although the age of onset of these sequalae were variable (varying between eight-weeks and 30-weeks of life), mitochondrial dysfunction was evident, identifying a point for therapeutic intervention. As such, we investigated the efficacy of daily Idebenone treatment (a powerful antioxidant and mitochondrial Co-Q10 analogue) against mitochondrial dysfunction and thus CI-SMDW. Idebenone co-therapy greatly improved mitochondrial performance in chemotherapy- treated mice, as well as protecting against lean mass loss and improving overall strength in the more aggressive chemotherapy regimen used against NHBL. Moreover, Idebenone co- therapy was shown to completely abate chemotherapy-induced mortality in the NHBL regimen, reducing mortality from 77% to zero. This thesis shows that childhood chemotherapy, regardless of the aggressiveness of the regimen or the classes of drugs used, induces life-long SMDW which is likely contributed to by mitochondrial dysfunction. The mitochondrial targeting therapeutic, Idebenone, shows promising potential for clinical application against the SMDW sequalae and mortality induced by some regimens, with the potential to improve childhood chemotherapy patient outcomes and survivability.

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