Elsevier

Leukemia Research

Volume 31, Issue 1, January 2007, Pages 19-26
Leukemia Research

Clinical response of myelodysplastic syndromes patients to treatment with coenzyme Q10

https://doi.org/10.1016/j.leukres.2006.04.009Get rights and content

Abstract

The myelodysplastic syndromes (MDS) are a collection of hematopoietic disorders with varying degrees of mono- to trilineage cytopenias and bone marrow dysplasia. In recent years much progress has been made in the treatment of MDS and there are now several therapeutic compounds used with varying levels of success. These compounds typically cause side effects that make them unattractive for treatment of patients in the early stages of MDS. Naturally occurring compounds that are not toxic may provide a means to treat patients in the initial stages of disease. We conducted a pilot study to test the efficacy of coenzyme Q10 (coQ10) in MDS patients with low to intermediate-2 risk disease. A variety of responses were observed in 7 of 29 patients including two trilineage and two cytogenetic responses. Sequencing mitochondrial DNA (mtDNA) from pretreatment bone marrows showed multiple mutations, some resulting in amino acid changes, in 3/5 nonresponders, 1/4 responders and in two control samples. We conclude that coQ10 may be of clinical benefit in a subset of MDS patients, but responders cannot be easily pre-selected on the basis of either the conventional clinical and pathologic characteristics or mtDNA mutations.

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.

Section snippets

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

References (12)

There are more references available in the full text version of this article.

Cited by (5)

View full text