P N M Cheng

The Hong Kong Polytechnic University, Hong Kong, Hong Kong

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Publications (3)15.87 Total impact

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    ABSTRACT: Melanoma has been shown to require arginine for growth, thus providing a potential Achilles' heel for therapeutic exploitation. Our investigations show that arginine depletion, using a recombinant form of human arginase I (rhArg), efficiently inhibits the growth of mammalian melanoma cell lines in vitro. These cell lines are consistently deficient in ornithine transcarbamylase (OTC) expression, correlating with their sensitivity to rhArg. Cell cycle distribution of A375 human melanoma cells treated with rhArg showed a remarkable dual-phase cell cycle arrest in S and G₂/M phases, in contrast to the G₂/M single-phase arrest observed with arginine deiminase (ADI), another arginine-degrading enzyme. rhArg and ADI both induced substantial apoptosis in A375 cells, accompanied by global modulation of cell cycle- and apoptosis-related transcription. Moreover, PEGylated rhArg dramatically inhibited the growth of A375 and B16 melanoma xenografts in vivo. Our results establish for the first time that (PEGylated) rhArg is a promising candidate for effective melanoma treatment, with fewer safety issues than ADI. Insight into the mechanism behind the antiproliferative activity of rhArg could inform us in designing combination therapies for future clinical trials.
    Pigment Cell & Melanoma Research 10/2010; 24(2):366-76. · 5.84 Impact Factor
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    ABSTRACT: Human hepatocellular carcinoma (HCC) has an elevated requirement for arginine in vitro, and pegylated recombinant human arginase I (rhArg-PEG), an arginine-depleting enzyme, can inhibit the growth of arginine-dependent tumors. While supplementation of the culture medium with ornithine failed to rescue Hep3B cells from growth inhibition induced by rhArg-PEG, citrulline successfully restored cell growth. The data support the roles previously proposed for ornithine transcarbamylase (OTC) in the arginine auxotrophy and rhArg-PEG sensitivity of HCC cells. Expression profiling of argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and OTC in 40 HCC tumor biopsy specimens predicted that 16 of the patients would be rhArg-sensitive, compared with 5 who would be sensitive to arginine deiminase (ADI), another arginine-depleting enzyme with anti-tumor activity. Furthermore, rhArg-PEG-mediated deprivation of arginine from the culture medium of different HCC cell lines produced cell cycle arrests at the G(2)/M or S phase, possibly mediated by transcriptional modulation of cyclins and/or cyclin dependent kinases (CDKs). Based on these results, together with further validation of the in vivo efficacy of rhArg-PEG against HCC, we propose that the application of rhArg-PEG alone or in combination with existing chemotherapeutic drugs may represent a specific and effective therapeutic strategy against HCC.
    Cancer letters 02/2009; 277(1):91-100. · 5.02 Impact Factor
  • P N M Cheng, Y C Leung, W H Lo, S M Tsui, K C Lam
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    ABSTRACT: Hepatocellular carcinoma (HCC) is auxotrophic for the semi-essential amino acid arginine, depletion of which leads to tumor death. In humans, arginine is not an essential amino acid since many adult somatic cells can re-synthesize it from other sources, such as citrulline. Enzymes capable of depleting arginine in vitro include the urea cycle enzyme arginase, which is found in abundance in human liver. For over three decades, arginase has not been considered as a potential drug candidate because of its low substrate affinity, short circulatory half-life and sub-optimal enzymatic activity at physiological pH, though its in vitro anti-tumor activities in certain tumors have been amply reported. Arginine deiminase, a bacterial enzyme from Mycoplasma hominus has been shown to induce HCC remission through the mechanism of arginine depletion. We report here an innovative treatment approach for the treatment of locally advanced and metastatic HCC with transhepatic arterial embolisation (TAE) of the liver tumor with lipiodol and gel foam as a means of inducing a leakage of hepatic arginase from the liver into the circulation. Hepatic arginase released into the systemic circulation rapidly depleted plasma arginine. High-dose insulin was included to induce a state of hypoaminoacidaemia to augment arginine depletion. With this protocol, we have treated seven patients with locally advanced and/or metastatic HCC. Five patients achieved arginine depletion, ranging from 0 to 20 microM (normal plasma level 100-120 microM); all had varying degrees of tumor remission in their primary tumors and extra-hepatic sites in the lymph nodes, lungs and bones, suggesting systemic anti-cancer effect of arginine depletion. The two non-responders did not show significant reduction in plasma arginine. Based on our findings, we propose that the urea cycle enzyme, arginase, is a good drug candidate for the treatment of HCC.
    Cancer Letters 07/2005; 224(1):67-80. · 5.02 Impact Factor

Publication Stats

53 Citations
15.87 Total Impact Points

Institutions

  • 2005
    • The Hong Kong Polytechnic University
      • Department of Applied Biology and Chemical Technology
      Hong Kong, Hong Kong