Terra Sigillata

The weekly NCI Cancer Bulletin recently featured a clinical trial being led by MD Anderson Cancer Center in Houston where the supplement, alpha-lipoic acid, is being investigated to minimize the peripheral neuropathy associated with platinum-based chemotherapy such as cisplatin or oxaliplatin.

Peripheral neuropathy is an unpleasant side effect of platinum-based chemotherapy that is characterized by a burning, numbness, and or tingling in the extremities. The acute form of the syndrome resolves a few days after the platinum treatment but sometimes persists. A similar syndrome occurs in patients with diabetes and alpha-lipoic acid supplements have been used with success in European-based studies to treat diabetic neuropathy.

Alpha-lipoic acid (sometimes called thioctic acid in the older literature) is itself a co-factor in aerobic respiration of the mitochondria (in the pyruvate dehydrogenase complex). The supplement consists of two forms, called enantiomers, with only one form able to act in the mitochondria. The genesis of peripheral neuropathy is complex but is hypothesized to result from altered neuronal bioenergetics and inadequate ATP levels for normal neurotransmitter release but can also result from physical damage to nerves or neurodegenerative disorders.

One previous Austrian trial illustrates that benefits are likely to require some duration of intravenous treatment. Therefore, the current trial will investigate whether only oral administration of alpha-lipoic acid can reduce the symptoms of peripheral neuropathy.

As with any treatment designed to reduce chemotherapy side effects, the major concern with alpha-lipoic acid is that it does not interfere with the beneficial anticancer effect of platinum drugs.

However, I was unable to find any literature even testing alpha-lipoic acid and platinum drugs against tumor cells in culture. I suspect that the IRB for this trial would have asked for such data before approving the protocol, so perhaps such data will be published shortly. One study with another anticancer drug, doxorubicin, suggests that combination with alpha-lipoic acid is antagonistic in leukemia cells except at very high levels that most likely cannot be achieved with supplementation

What I did find interesting is that alpha-lipoic acid is being investigated for its own anticancer activities, for reasons that seem counterintuitive. For example, alpha-lipoic acid has antioxidant activity and is known to help regenerate vitamin C and vitamin E when they are oxidized in the body. Two recent studies, however, suggests that high levels of alpha-lipoic acid can cause increased oxidative stress in tumor cells grown in culture. Alpha-lipoic acid also seems to block DNA synthesis and trigger the enzymatic cascade leading to tumor cell death, or apoptosis.

Again, as I say with any cell culture study, these effects occur at very high concentrations that may not be achievable in actual patients; remember that some trials of alpha-lipoic acid require that it be administered by injection rather than orally in order to achieve high concentrations.

But my interest is always piqued when I see counterintuitive results such as these. An agent that protects against a chemotherapeutic side effect is certainly valuable, especially if it does not interfere with the desired anticancer effect of the drug in question. Given the potential of alpha-lipoic acid to cause unexpected cancer cell death in culture, I look forward to results of the peripheral neuropathy study. One would hope that secondary measures of patient tumor response are also monitored so we can gain some indication as to whether alpha-lipoic acid enhances or interferes with chemotherapeutic drug efficacy.