Clinical response of myelodysplastic syndromes patients to treatment with coenzyme Q10
Introduction
The myelodysplastic syndromes (MDS) are a collection of hematopoietic disorders characterized by anemia, variable cytopenias, and bone marrow dysplasia. Several treatments such as differentiating/hypomethylating agents (5-azacytadine), immunomodulatory compounds (thalidomide and Revlimid), farnesyl transferase inhibitors, and others are currently approved or in clinical trials (reviewed in [1] and [2]). However, management of transfusion-independent patients with MDS has not been extensively examined, treatment being typically withheld until patients either become transfusion-dependent or show signs of disease progression. Intervention at the early stage may require the use of agents with possible serious side effects, and this risk outweighs the potential benefit. Intuitively then, treatment with nontoxic substances, which may take longer to show benefit, may be effective at the early stages of the disease.
Coenzyme Q10 (coQ10), a lipid-soluble molecule found in all cellular membranes and serum, is involved in multiple pathways essential for growth and homeostasis. CoQ10 is an essential component of the mitochondrial respiratory chain [3], can inhibit cytochrome c induced apoptosis [4], [5], and is a powerful antioxidant in its reduced form [6]. This last activity is especially important since mitochondria generate high levels of reactive oxygen during the synthesis of ATP that damage lipids, proteins, and DNA. Decreased levels of coQ10 have been reported to occur with age, the use of certain drugs, and with cancer [7]. Low dose coQ10 therapy has been attempted in several diseases involving mitochondrial dysfunction with little, if any, effect; however, most of these trials were of short duration using low doses of coQ10 [8], [9]. Notably, when high doses of coQ10 were administered over longer periods to patients with Parkinson's disease, a significant decrease in the rate of deterioration was observed [10].
The importance of mitochondria in the pathology of MDS has been recognized for some time [11], [12] suggesting that high dose coQ10 may be a useful therapeutic agent for this disease. In a study of 29 low-intermediate-2 risk MDS patients, high dose coQ10 administered for at least 16 weeks resulted in a variety of responses. We found that 7 of 29 patients responded to coQ10 treatment, including two trilineage responses, with no side effects. These results indicate that coQ10 may be an effective agent for MDS therapy with patients that are in the early stages of the disease. Sequence of the mitochondrial DNA (mtDNA) from bone marrow mononuclear cells of four responders, five nonresponders, and two normal volunteers revealed correlation between frequency or location of mtDNA mutations and response.
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Patients and treatment
A total of 29 patients were enrolled in the study to test the efficacy of coQ10 in improving the cytopenias of MDS as approved by the Institutional Review Board of Rush-Presbyterian, St. Luke's Medical Center, Chicago, IL. Consecutively seen newly and previously diagnosed patients were eligible, with either primary de novo or secondary MDS. Patients received 1200 mg/daily of coQ10 formulated in wafers of 300 mg (Enzymatic Therapy Inc.). Treatment was given for a minimum of 16 weeks. CBC's were
Patient response to coQ10
A total of 29 patients were enrolled in the coQ10 study. The median age of all the patients enrolled in this study was 71 years (30–81). There were 18 males and 11 females with 7 having low, 20 having intermediate-1, and 2 having intermediate-2 risk MDS (Table 1). Fifteen patients had a French–American–British (FAB) classification of refractory anemia (RA), four with refractory anemia with ringed sideroblasts (RARS), three with refractory anemia with excess blasts (RAEB), two with chronic
Seven patients responded to coQ10, a nontoxic naturally occurring substance
CoQ10 is an important antioxidant that is involved in the generation of ATP and the regulation of apoptosis within mitochondria. We performed a phase I clinical trial to ascertain the benefit of treatment with coQ10 supplements to patients with low- to intermediate-risk MDS. Twenty-nine patients were enrolled in the study and seven showed a wide range of responses including trilineage and monolineage responses, cytogenetic responses, and changes in FAB classification. These results are very
Acknowledgements
This work was supported by The Radhey Khanna MDS Center and the Shayamalan Foundation. The coQ10 was donated by Enzymatic Therapy Inc., Green Bay, Wisconsin.
Contributions. Naomi Galili was the research director for this project, analyzed the data, and contributed to the writing of this manuscript. Eric V Sechman performed the mtDNA analysis and contributed to the writing of this manuscript. Jan Cerny performed statistical analysis of the results of the clinical trial. Murtaza Medhi assisted in
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