Re: Neurocognitive Functioning in Adult Survivors of Childhood Noncentral Nervous System Cancers

Extract

Kadan-Lottick et al. ( 1 ) recently published an article in the Journal on the analysis of neurocognitive functioning in adult survivors of childhood noncentral nervous system cancers, in which they concluded that there is a statistically significant higher percentage of neurocognitive functioning impairment among these adult survivors than among their siblings. They found that radiation therapy and also chemotherapy (mostly with methotrexate, which hinders DNA synthesis) of noncentral nervous system cancers are associated with delayed impairment in task efficiency ( 1 ). Albini et al. ( 2 ) showed in the Journal that cancer chemotherapeutic agents (eg, 5-fluorouracil, capecitabine, and cytarabine) also cause cardiotoxicity, an increasingly relevant toxic side effect of this therapy.

A stronger association among patients with breast cancer treated with 5-fluorouracil chemotherapy and impairment of cognitive capacities was reported by Schagen et al. ( 3 ) in the Journal. In addition, Han et al. ( 4 ) reported that systemic 5-fluorouracil treatment causes myelin destruction in the central nervous system. Specifically, they showed that both precursor and mature oligodendrocytes, rather than astrocytes, are targets of the cytotoxic activity of 5-fluorouracil. Precursor and nondividing mature oligodendrocytes were more sensitive to 5-fluorouracil than dividing cancer cells. More recently, Schoenfeld et al. ( 5 ) found that oligodendroglia were extremely sensitive to rotenone, a classic inhibitor of mitochondrial oxidative phosphorylation, and that mitochondrial DNA was amplified during oligodendroglial differentiation, which may explain the sensitivity of differentiating oligodendroglia to rotenone. An impressive increase in the level of mitochondrial proteins in differentiating oligodendrocytes was shown by Cordeau-Lossouarn et al. ( 6 ), who observed that even though the levels of mitochondrial proteins increased in these cells, the number of mitochondria remained constant. These results establish a link between myelin sheath construction and mitochondrial proliferation because oligodendrocytes produce myelin in the central nervous system. In fact, mitochondrial DNA, which has a higher turnover than nuclear DNA, is more likely to be sensitive to antimetabolites that inhibit DNA synthesis than nuclear DNA. Therefore, cells with high mitochondrial turnover, such as oligodendrocytes ( 5 ), are more likely to be sensitive to antimetabolites that inhibit DNA synthesis.