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    Melanoma Fighter

    Enzyme has anti-tumor activity in metastatic melanoma

    Chicago - Arginine deiminase, an amino acid degrading enzyme, is safe and has anti-tumor activity in phase I and II investigations of metastatic melanoma, according to Theodore Logan, M.D.

    In a phase I-II trial, six of 26 patients (23 percent) had a response; investigators say there were no observable toxicity related to decreased serum arginine levels.

    "Further testing of this agent in melanoma is warranted," said Dr. Logan, associate professor of clinical medicine, Indiana University School of Medicine, Indianapolis, Ind.

    Research StudyHere at the 39th annual meeting of the American Society of Clinical Oncology, the investigator described an initial U.S. phase I study in which 15 patients were treated; two patients had stable disease for a short period of time, and the subsequent phase I-II trial, that is being conducted in Italy.

    Enzyme LackingArginine is thought to be essential for melanoma cells but not for humans. In humans, arginine is metabolized by arginase to urea and ornithine; subsequently, ornithine is metabolized into citrulline, Dr. Logan said. Then, citrulline can be metabolized through arginosuccinate synthetase back through to arginine.

    By contrast, human melanoma cell lines are unable to express argininosuccinate synthase, and so cannot convert citrulline into arginine.

    "Melanoma cell lines, greater than 30 at this counting, lack the enzyme arginosuccinate synthetase, so effectively arginine is an essential amino acid for melanoma cell lines," Dr. Logan said."The same seems to be true for liver cancer cell lines."

    Arginine Deiminase EffectsDr. Logan and colleagues are now evaluating the effects of arginine deiminase in patients with metastatic melanoma.

    In the formulation under study, arginine deiminase is conjugated with polyethylene glycol. In animals, this formulation increases the circulating half-life and decreasing the immunogenicity of the amino acid degrading enzyme.

    Arginine deiminase, found naturally in microplasma, has the function of metabolizing arginine to citrulline, Dr. Logan said. It is available in recombinant form from mycoplasma, and is expressed in ecoli.

    American StudyThe peg formulation was described in the 1980s, but in this study Clark et al have described the 20,000 molecular weight peg formulation of ADI.

    In the American phase I study, doses of 20, 40, 80 and 160 IU/m2 were given on days one, 15 and 22, for a single cycle, in 15 patients with measurable, histologically confirmed metastatic melanoma that was progressive and unresectable.

    The study, now complete, evaluated safety, pharmacokinetics, immunogenicity and efficacy.

    Italian StudyThe subsequent Italian phase I-II investigation has evaluated doses of 20 to 320 IU/m2 as a continuous weekly treatment; on the other hand, the phase II dose selected in this ongoing study is 160 IU/m2.

    Twenty-six patients were enrolled, and six partial responses have been noted thus far.

    Those responses occurred in patients treated at higher doses. Responses were mostly in skin lesions and were evident after two to four months of treatment.

    Together, those studies include 41 melanoma patients who have received a total of 521 treatments.

    In a separate series, 29 liver cancer patients have received 819 treatments; in this group there has been one grade 3 toxicity (hypotension) but there have been no other adverse events of grade 2 or greater attributed to the drug, according to Dr. Logan.

    Clinical ResponseClinical response appeared to correlate directly with patients' plasma arginine concentrations.

    Several patients have been treated at doses of 320 IU/m2; however, with the 160 IU/m2 dose, arginine levels were "essentially taken to 0 for a prolonged period of time" and subsequent patients are being treated at 160 IU/m2.

    "A number of patients have been treated for greater than three months without detectable serum arginine with no ill effect," Dr. Logan said.

    Antibodies were measured against the agent; they were found to be of low titer (< 102) and thought to be clinically insignificant. Investigators have observed no allergic reactions.

    Unanswered QuestionsScott Saxman, M.D., of the National Cancer Institute, said that there "remain some unanswered questions" regarding the use of this agent in metastatic melanoma.

    For example, it's not known that human melanomas in vivo are devoid of arginosuccinate synthetase. Thus far, the only studies are in murine and human cell lines, not actual human tumors.

    In addition, the mechanism of loss of expression of the enzyme isn't known, and initial studies of the gene have not revealed any defect that could be responsible.

    It is possible that absence of the enzyme in the tumor may predict for response, and could be a patient selection criteria for future studies.

    "That's not known yet, but as translational studies are done in the context of phase II trials, I think that will become apparent," Dr. Saxman said.

    Andrew Bowser
    Andrew Bowser is a medical writer based in Brooklyn, New York.

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