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Hyperhomocysteinemia is a risk factor for cancer and a new potential tumor marker

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Abstract

Plasma homocysteine (Hcy), a well-known independent risk factor for coronary heart disease, is also a risk factor for cancer. Results from our studies indicate that Hcy could be used as a tumor marker. We found elevated circulating total homocysteine (tHcy) in cancer patients even though they were not treated with anti-folate drugs. In serial specimens from cancer patients undergoing treatment, the change of tHcy coincided with the concentration of tumor markers. The rapid proliferation of tumor cells contributed to the much higher concentrations of circulating tHcy. Both concentrations of tHcy and tumor marker would increase in parallel during the growth of tumor cell, but only the Hcy concentration would decline in response to tumor cell death. Several biochemical changes, including folate deficiency, oxidative stress, aberrant DNA methylation, and production of homocysteine thiolactone have been identified in association with hyperhomocysteinemia, which explained why elevated homocysteine eventually led to carcinogenesis. Conceivably, tHcy may be used as a more accurate tumor marker for monitoring cancer patients during treatment, and hyperhomocysteinemia as a risk factor for carcinogenesis.

Introduction

Homocysteine is largely derived from cellular methionine, an essential amino acid drawn from dietary intake. Intracellular homocysteine is normally secreted extracellularly, at rapid rates. Consequently, the concentration of homocysteine in the plasma and urine reflects the balance between intracellular homocysteine production and utilization, while the blood concentration of homocysteine reflects the cellular homocysteine (Hcy) concentration [1].

In the circulating blood, the majority of the homocysteine binds to albumin, forming a disulfide linkage. Approximately 10% to 20% of the Hcy also exists as a mixed disulfide with cysteine or with homocysteine itself (Fig. 1). Very little Hcy is present in the circulating blood in a free reduced form (approximately 1%) [2], [3]. Current procedures employed for the measurement of plasma homocysteine concentrations measure the total concentration of homocysteine (tHcy), which includes albumin bound homocysteine, homocysteine in all of the disulfide linkages, and the free reduced form of homocysteine. It was correctly pointed out by Mudd and Levy [4] that the term homocyst(e)ine, not homocysteine, should be used to reflect the fact that in circulating blood, both reduced and oxidized forms exist. “Homocysteine” only represents the reduced form. However, just for the sake of convenience and simplicity, we use tHcy to represent all forms of “total homocysteine” in the circulation throughout this paper.

Section snippets

Normal level

According to Jacobsen [5], the normal range of plasma tHcy for “healthy adults” is 5–15 μmol/l; 15 to 25 μmol/l indicates mild hyperhomocysteinemia; 25 to 50 μmol/l is considered intermediate hyperhomocysteinemia and >50 μmol/l, severe. It was recommended that plasma tHcy be kept under 10 μmol/l.

Metabolic pathway involving homocysteine

It is much easier to understand the various conditions that lead to hyperhomocysteinemia and also the underlying biochemical mechanisms by examining the metabolic pathways involving homocysteine. As shown in Fig. 2, there are three major metabolic reactions involving homocysteine: remethylation, transsulfuration and transmethylation [6]. We now know that in most cases, anything that goes wrong involving these three reactions would alter homocysteine concentration and yield hyperhomocysteinemia.

As a new tumor marker

As shown in Fig. 4 in our earlier study, we were surprised to find so many cases of elevated serum tHcy in patients with breast, ovarian and pancreatic carcinoma who were not taking anti-folate drugs. One of the explanations related the elevation is to the rapid proliferation rate of tumor cells, as Ueland and Refsum [6] experienced with their leukemia patients. In fact, it has also been reported by Corona et al. [9] that elevated tHcy was found in the serum and cystic fluid of a patient with

As a risk factor

Several biochemical changes recently identified in association with hyperhomocysteinemia indicate that elevated tHcy in blood circulation creates a risk for cancer, and it is likely that hyperhomocysteinemia is a risk factor for carcinogenesis.

References (31)

  • D. Jacobsen

    Homocysteine and vitamins in cardiovascular disease

    Clin. Chem.

    (1998)
  • P.M. Ueland et al.

    Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy

    J. Lab. Clin. Med.

    (1989)
  • T. Lizasa et al.

    Differential regulation of polyamine synthesis and transmethylation reactions in methylthioadenosine phosphorylase deficient mammalian cells

    Biochim. Biophys. Acta

    (1985)
  • J. Wu et al.

    Human circulating tumor markers. Current concepts and clinical applications

    (1997)
  • I. Kato et al.

    Serum folate, homocysteine and colorectal cancer risk in women: a nested case-control study

    Br. J. Cancer

    (1999)
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