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Carnitine-Doxorubicin Clinical Study for the Treatment of Stages III-IV Ovarian Cancer
Carnitine is a naturally occurring safe substance found in most human cells. Orphan Drug NDA approvals of both the intravenous and oral forms were obtained by Sigma tau, Inc. a U.S. subsidiary of the Italian Company, Sigma tau S.p.A, for the Orphan Drug indications of primary and secondary carnitine deficiency as well as renal dialysis.
Carnitine has a number of actions. The two primary ones are the transport of fatty acids across mitochondrial membranes where they are metabolized to produce ATP and reducing or eliminating the toxic effects on the mitochondria by a wide variety of substances. There are a substantial number of preclinical and clinical publications to support these actions.
During the Vietnam War Major James Vick and I were stationed at WRAIR, the Walter Reed Army Institute of Research. He was a cardiovascular pharmacologist specializing in shock research, including those caused by toxins, and I, based, on my ongoing basic and clinical research experience with carnitine, was highly interested on its general shock reversal potential. At that time the government was- and, more than ever, still is interested in a number of toxins for both medical and national self- defense reasons. The Major and I decided to conduct a number of preclinical cardiovascular studies. Parenterally administered carnitine successfully prevented and treated myocardial ischemia, cardiac arrhythmias and congestive heart failure all of which findings have been subsequently confirmed and published in both preclinical and clinical studies. Cardiac carnitine levels are reduced in these states causing mitochondrial dysfunction. The administration of parenteral carnitine replenishes cellular levels restoring normal mitochondrial function and ATP production.
Regarding our studies on the toxins, E.coli toxin, Russell snake viper toxin, coral palytoxin and doxorubicin (Adriamycin), carnitine was given as treatment after lethal, shock producing doses were in effect. The administration of carnitine dramatically reversed all shock states.
The doxorubicin- induced acute shock state was primarily due to cardiotoxicity. We then wondered whether carnitine also blocked its cell kill capacity. In otherwords, it was a general inhibitor of doxorubicin. Fortunately, one of our colleagues, Sam Barranco, was a well respected cancer researcher with expertise in cell culture technology. He evaluated this possibility using Chinese hamster ovarian culture cells. Carnitine not only did not block doxorubicins cell killing capacity but synergistically increased it tenfold!
For a variety of reasons the major one being the lack of strong patents, it was difficult was to convince a pharmaceutical company to sponsor a clinical program to obtain an NDA. Time passed and, sparked by my experience of a 24 year old woman diagnosed with ovarian cancer, I decided to test the combination of the two drugs in human ovarian cancer culture cells because this is a preclinical model that is predictive of doxorubicins clinical efficacy.
The study was conducted at Vanderbilt University Medical Center. The results were extremely encouraging. Carnitine not only increased the cell killing capacity of doxorubicin but, surprisingly, also had a significant cell kill capacity of its own. It killed over 50% of the cells at dose levels which can be safely achieved in patients by intravenous administration.
Over the years I had lost contact with the carnitine cancer literature. When I called my long time friend and colleague, Dr. Claudio Cavazza, the proprietor of Sigma tau S.p.A, I discovered he had already supported a number of cancer related laboratory studies on carnitine and its relatives. Results were encouraging and dependent on the laboratory model. But the net effect was unequivocally positive regarding enhanced tumor cell kill capacity as well as anti- toxicity effects on chemotherapeutic agents.
Carnitine's Mechnism of Action
In a number of laboratory studies carnitine has been shown to induce apoptosis in cancer cells while having no effect on normal ones. There are two primary theories of carnitines anti-cancer activity which application depends on the type of cancer cell. One is based on data reporting that cancer cells limit the utilization of mitochondrial fatty acids as a fuel. Carnitine, which transports fatty acid across mitochondrial membranes, increases the fatty acid fuel supply to the cancer cells having a detrimental effect on the malignant cell leading to increased apoptosis. For example, in human colon cancer cells, carnitine increased fatty acid uptake resulting in a significant increase in apoptosis. No effect of carnitine on normal colon cells was found.
The second theory holds that carnitine induced apoptosis is related to a mitochondrion-dependent and death ligand/ receptor-dependent pathway. In mouse hepatoma cancer cells carnitine significantly induced apoptosis while it had no effect on normal cells.
There are other theories. For example, in breast cancer tumor bearing mice it is believed that cancerous mitotic activity is dependent on increased arginase and decreased nitric oxide activity. The administration of carnitine decreased arginase and increased nitric oxide activity while significantly decreasing mitotic counts.
Regarding carnitines ability to dramatically reduce doxorubicins cardiotoxicity as well as enhancing its tumor apoptotic activity, there may be two different mechanisms of action involved. In the non- malignant Chinese hamster cells, carnitine had no effect but when given with doxorubicin there was a synergistic apoptotic effect which bespeaks of one type of mechanism. When given to human ovarian cancer cells carnitine has its own significant apoptotic effect. When given with doxorubicin in this model it did increase the formers apoptotic effect but not synergistically which raises a number of possibilities.
Carnitine Studies Demonstrating That Carnitine Blocks Doxorbicin's Cardiotoxicity
Since Major Vick and I conducted the first experiment observing that carnitine impressively blocked doxorubicin-induced cardiotoxicity there have been dozens of preclinical studies, acute, subacute and chronic, which have confirmed our findings.
There are a number of clinical studies which, mainly employing the EKG and blood enzymes, which report that carnitine blocks the acute cardiac effects of doxorubicin. It, however, is commonly accepted that these acute effects are not predictive of the ones that lead to chronic cardiomyopathy.
Though not definitive in design, there is one clinical study evaluating forty patients with non-Hodgkins lymphoma that addresses the latter possibility. Echocardiography was employed to evaluate cardiac function. There were no deleterious changes over a three month period in those treated with carnitine and doxorubicin. In addition, molecular mitochondrial measurements supported these findings. Both mitochondrial RNA and oxidation were increased.
Carnitine's Relatives and Other Chemotherapeutic Agents
There is the possibility that carnitine may also increase the anticancer activity of other chemotherapeutic agents. For example, acetylcarnitine (ALC) and proprionylcarnitine (PLC) are mostly converted to carnitine. In mouse leukemia which is resistant to mitoxantrone, ALC alone had no effect but when given with mitoxantrone it significantly prolonged survival time. PLC increased the anti- cancer activity of taxol when administered to mice with breast cancer tumors.
Clinical Studies Reporting Carnitine Deficiency in Both Adult and Pediatric Cancers
In an adult population of cancer patients with fatigue, 78 percent of this population was reported as carnitine deficient. In a pediatric cancer population it was reported that carnitine deficiency exists and is not due to dietary input but to the cancer process itself and/or chemotherapeutic treatment. These findings indirectly support the preclinical results that carnitine deficiency may play a role in increased apoptotic malignant cell proliferation as well as contribute to the toxic effects of chemotherapeutic agents.
Carnitines Broad Anti-Toxicity Profile Versus its Anti-Cancer One
It is interesting to note that the results of studies that evaluated the anti-toxicity properties of carnitine are consistently positive while those evaluating it anti-cancer effects- whether alone or in given with chemotherapeutic agents- depend on the type of cancer and the experimental model used. In addition to the toxins evaluated by us at WRAIR some other examples are that carnitine blocks the toxicity of formaldehyde, diphtheria, methotrexate, AZT (zidovudine) and carboplatinum. The most reported beneficial effects have been on cardiac and neuronal cells. The same holds true with ALC and PLC.
Toxins, either directly or indirectly, negatively impact mitochondrial function. Carnitines dual mechanism of action on the mitochondria most likely accounts for its anti-toxicity activity.
There is then this intriguing possibility: in certain malignancies carnitine may have an a) anti-toxicity effect but not an anti-cancer one or b) both types of activity. In addition, the data indicate that the anti-cancer dose of carnitine is significantly higher than the anti-toxicity one which may explain the differences in activity. This possibility must be considered in clinical studies.
From a clinical point of view, in the preclinical models carnitine is effective both as treatment and prevention. Because carnitine is a generic drug it is highly improbable that a costly, long term clinical prevention study will be done. Generally speaking, treatment studies, however, are much less costly and can be done relatively quickly. Since carnitine is already an FDA approved drug with an enviable safety profile, and since there are millions of cancer patients living with the toxic effects of chemotherapeutic drugs, an interested clinical investigator would find it less difficult to take the treatment approach.
The Ongoing Clinical Study With Carnitine and Doxorubicin in Stages Iii-Iv Ovarian Cancer
This patient population was selected based on a number of complex factors. Bottom line, we are searching for an obvious effect in a small, specific cancer patient population. If carnitine is found to be effective in these patients, then it will hold promise for others. The patient population chosen are those in late stages of ovarian cancer where cancer cells have become resistant to platinum-taxane therapy a small percentage of whom, however, are known to respond to doxorubicin. The study has recently begun and patient recruitment is ongoing.
Rationale For The Hope
The hope is based on six points: The first is that in this population though minimal, there is a tumor size reduction response to doxorubicin. The second is based on the unique synergistic effect of carnitine on doxorubicins cell kill capacity in Chinese hamster ovarian culture cells. The third is based on carnitines impressive apoptotic effect on human ovarian cancer culture cells. The fourth is based on doxorubicins cell killing effect on human ovarian cancer culture cells which is a model that is predictive of the drugs effectiveness in clinical studies. The fifth is based on the carnitines ability to increase the tumor kill capacity of doxorubicin in these same cells. The sixth is that both the reduction of toxicity and increased tumor cell apoptosis may enhance the effectiveness of the immune system and other body defenses.
Stephen L. DeFelice, M.D.
February 1, 2009
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