Acute lymphoblastic leukemia (ALL) is a cancer of leukocytes that is responsible for thousands of deaths in the US each year. Although pediatric patients are the most common developers of ALL, nearly 80% of ALL deaths occur in adult patients. This is at least in part because of differential treatment of ALL in pediatrics and adults. Pediatric bodies are more adaptive, and can often withstand stronger chemotherapy than adult patients. L-asparaginase is a chemotherapeutic which is often used in combination therapy to treat ALL. However, it is largely avoided in adult patients due to its adverse effect profile, which includes hypersensitivity, clotting disorders, pancreatitis, and hepatotoxicity.
L-carnitine is an amino acid derivative which is used for transport of fatty acids across the mitochondrial membrane, where they can then be oxidized for energy. It has been implicated in reducing drug-induced toxicity from a number of other drugs, including HIV medications. A study done in Germany investigated the effects of L-carnitine administration on liver damage in diet-induced liver steatosis in rats treated with asparaginase.
Liver steatosis was induced in rats by providing a carbohydrate enriched and fat free diet, producing mild-to-moderate (30-40%) steatosis in the liver. Rats were then anesthetized and their livers were harvested and reperfused in vitro for 120 minutes. L-asparaginase was the added to the reperfusion. Hepatic effluent was collected at 5, 15, 30, 45, 60, 75, 90, 105, and 120 min post-reperfusion and analyzed for biomarkers of liver toxicity (AST, GLDH, and LDH). On the second day, the perfusion was moved to fresh medium containing various amounts of asparaginase and L-carnitine. Remarkably, biomarkers of liver damage decreased for all tissue treated with L-carnitine.
Adverse effects associated with chemotherapeutics are one of the major limitations of drug-based cancer treatments. As chemotherapeutics are literally designed to kill cells (albeit, hopefully only cancerous ones), reduction in these adverse effects via only modification of the drug may risk losing anti-cancer efficacy. Therefore, pre-treatments are an important option for maintaining optimal chemotherapeutic efficacy while mitigating adverse effects in the treatment of cancer patients. Therefore, identification of compounds which may have the potential to reduce or reverse adverse effects is critical in optimizing cancer therapy. With more evidence, L-carnitine may be able to be used in human clinical trials to rescue hepatotoxic effects from ALL administration.
Do you guys think that using more drugs to rescue the adverse effects of another drug is a viable therapeutic approach? Or rather, should we invest our research in producing de novo drugs with an intrinsic reduction in adverse effects? What are the benefits and limitations of each approach?