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LResearch Newsletter-Spring/Summer 2010


Debbie J. Mustacich, Ph.D.
Assistant Professor (Senior Research),
Linus Pauling Institute and
OSU Department of Biomedical Sciences

The American Cancer Society estimates that more than 1.4 million new cases of cancer were diagnosed and more than 500,000 people died of cancer-related deaths in the United States during 2008. Lung cancer accounts for 29% of all cancer deaths and is the leading cause of cancer deaths in both men and women. Non-small-cell lung cancer (NSCLC) accounts for 75-80% of lung cancers and has a five-year survival rate of ~15%. In women, ovarian cancer has the highest mortality rate of all the female reproductive system cancers, accounting for 6% of all cancer-related deaths in women. The high death rate for both of these cancers is due, in most cases, to patients having advanced disease at the time of diagnosis. In contrast, prostate cancer is often diagnosed in the early stages when the tumors are responsive to androgen ablation therapy. However, over time prostate cancers nearly always undergo androgen-independent progression and become refractory to hormonal manipulation such that prostate cancer remains the second leading cause of cancer-related deaths in men. These dismal statistics indicate a need for innovative improvements in treatment modalities, particularly with respect to improved therapies for patients with advanced stage cancer.

Why use cisplatin?

Cisplatin, a platinum-containing compound, is currently one of the most effective anticancer drugs available for treating a variety of solid tumors, including lung, ovarian and prostate cancer. Cisplatin-based chemotherapy has been shown to significantly increase overall survival rates when used as adjuvant treatment in NSCLC patients following lung resection surgery, particularly in late-stage cancer. In addition, clinical trials have demonstrated an increased response and median survival in hormone refractory prostate cancer (HRPC) patients treated with therapies that include platinum compounds. In 2006, the National Cancer Institute recommended that the standard treatment for women with late-stage ovarian cancer should be surgical removal of the bulk of the tumor followed by intraperitoneal (IP) injection of cisplatin in combination with a taxane, such as paclitaxol, given either IP or intravenously (IV). Use of IP cisplatin in ovarian cancer patients increased median survival by 16 months compared to IV cisplatin. Compared to IV administration, IP administration of chemotherapy drugs allows longer exposure of the peritoneal cavity, the principal site of disease in ovarian cancer, to higher doses of the drug. Unfortunately, like many other anticancer agents, platinum compounds are neurotoxic, and development of peripheral sensory neuropathy often limits the dose and duration of treatment. Notably, neurologic side effects occurred at a higher rate in patients receiving IP cisplatin such that most patients receiving IP cisplatin did not complete as many treatment cycles as patients receiving IV cisplatin. The mechanism of cisplatin neurotoxicity remains unknown, thus hampering the development of optimal adjuvant treatments to prevent platinum-induced neuropathy and allow patients the full life-extending benefits of cisplatin treatment without the debilitating side effects that reduce quality of life.

Similarities between cisplatin toxicity and vitamin E deficiency neuropathies

Vitamin E deficiency occurs rarely in humans. When it does, it is usually the result of a genetic abnormality in the alpha-tocopherol transfer protein or a fat malabsorption syndrome. A distinct pattern in the progression of neurological symptoms resulting from vitamin E deficiency in humans has been described, with symptoms characterized by ataxia (loss of muscle coordination), paresthesia (prickling, tingling sensation), and loss of reflexes. These symptoms result from a loss of the large caliber axons of the sensory neurons. Pathologic studies indicate that the dorsal root ganglia are the neural tissue primarily affected by vitamin E deficiency. Remarkably, the description of neuropathy in cancer patients treated with cisplatin closely resembles that of human vitamin E deficiency. In one study, 10 of 11 ovarian cancer patients receiving cisplatin developed a distal sensory neuropathy, manifested by decreased vibratory sensation—the first detectable symptom in vitamin E deficiency. With continued cisplatin therapy, four patients developed paresthesia. At autopsy, platinum levels were highest in the dorsal root ganglia, as compared to other neural tissue, the same nervous tissue affected by vitamin E deficiency.

Benefits of vitamin E supplementation during cisplatin treatment

Many anticancer drugs cause oxidative stress in normal tissues while killing cancer cells via non-oxidative stress mechanisms. Importantly, cisplatin-based regimens have been shown to decrease plasma vitamin E (alpha-tocopherol) levels in patients. Thus, antioxidants, including vitamin E, may represent an important adjuvant to standard chemotherapy regimens. However, clinical trials investigating the use of alpha-tocopherol in combination with chemotherapeutic drugs have been sparse, in part due to the concern that antioxidant vitamins, due to their ability to prevent oxidative stress generated by free radicals, may reduce the efficacy of some anticancer drugs. However, numerous cell culture studies have found that vitamin E, particularly at high pharmacologic doses, potentiates the apoptotic (programmed cell death) and growth inhibitory effects of anticancer drugs, including platinum compounds.

Ongoing studies

Our central hypothesis is that 1) cisplatin depletes alpha-tocopherol in the lumbar region of the spinal cord, specifically the dorsal root ganglion, by an oxidative stress mechanism whereby platinum acts as a catalyst for lipid peroxidation resulting in an alpha-tocopherol-deficiency neuropathy; 2) pharmacologic doses of alpha-tocopherol will prevent the cisplatin-mediated alpha-tocopherol depletion, thereby preventing the neurologic side effects of cisplatin; and 3) alpha-tocopherol supplementation will not decrease the anticancer efficacy of cisplatin.

We first determined that daily administration of pharmacologic doses of alpha-tocopherol to rats significantly increased alpha-tocopherol levels in tissues, including liver (~15-fold), lung (~3-fold), kidney (~2-fold), spinal cord (~2- fold), and dorsal root ganglia (~2-fold). Next, we treated rats with three cycles of five daily injections of either cisplatin or placebo with and without co-administration of pharmacologic doses of alpha-tocopherol. As expected, lipid peroxidation significantly increased and dorsal root ganglia alpha-tocopherol levels significantly decreased in cisplatintreated rats. Importantly, concurrent high-dose alpha-tocopherol administration preserved dorsal root ganglia alphatocopherol levels and prevented increased lipid peroxidation in cisplatin-treated rats. Future studies to further elucidate the mechanism of cisplatin-induced neuropathy, as well as determine the efficacy of adjuvant high-dose alpha-tocopherol, will determine 1) the ability of cisplatin to alter the plasma and tissue levels of additional antioxidants; 2) the ability of alpha-tocopherol to prevent the morphological changes in dorsal root ganglia associated with cisplatininduced neuropathy; and 3) the anticancer efficacy of cisplatin in tumor-bearing rats given pharmacologic doses of alpha-tocopherol.

Understanding the mechanism of cisplatin-induced neuropathy, as well as determining the ability of alphatocopherol to prevent the biochemical and morphologic changes associated with cisplatin-induced neuropathy without decreasing anticancer efficacy, will provide the necessary evidence-based knowledge to support clinical trials to determine guidelines for including vitamin E in cisplatin-based chemotherapy regimens. Preventing cisplatininduced neuropathies will allow patients to complete, and possibly increase, their cisplatin treatments; thus allowing patients to fully benefit from the life-extending potential of long-term cisplatin treatment without the debilitating side effects that currently reduce quality of life for both patient and family.

Last updated June 2010