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Plasma amino acid concentrations in patients with acute myelogenous leukemia
APPLIED NUTRITIONAL INVESTIGATION
Nutrition Vol. 15, No. 3, 1999
Plasma Amino Acid Concentrations in Patients With Acute Myelogenous Leukemia M. MUSCARITOLI, MD, L. CONVERSANO, MD, M. C. PETTI, MD, A. CASCINO, MD, S. MECAROCCI, MD, M. A. ANNICCHIARICO, MD, AND F. ROSSI FANELLI, MD From the Departments of Clinical Medicine and Human Biopathology, Hematology, University “La Sapienza,” Rome, Italy Date accepted: 11 May 1998 ABSTRACT
Changes in plasma-free amino acid (PFAA) concentrations in the presence of solid tumors have been widely described. Conversely, the PFAA profile in patients with acute leukemias is less well defined. The aim of the present study was to clarify whether the PFAA profile is altered in patients with acute myeloid leukemia (AML), whether the profile differs from the PFAA profile of solid tumors, and whether it may predict outcome of AML. Fasting PFAA were measured in 40 untreated, normally nourished patients with AML (17 males, 23 females), ages 22–78 y, with white blood cell (WBC) counts ranging from 1.08 to 276.5 3 103/cm2, and in 24 healthy volunteers. Plasma concentrations (mmol/L, mean 6 SE) of glutamic acid (GLU), free tryptophan (FTRP), ornithine (ORN), and glycine (GLY) were significantly higher in AML (GLU: 90.2 6 6.1 versus 37 6 8; FTRP: 7.0 6 0.6 versus 4.8 6 0.3, P , 0.005; ORN: 108.7 6 5.8 versus 78 6 6, P , 0.001; GLY: 295.0 6 14.8 versus 239 6 9, P , 0.01), whereas serine (SER), methionine (MET), and taurine (TAU) were significantly lower in AML than in controls (SER: 109.0 6 5.8 versus 130 6 4, P , 0.03; MET: 25.5 6 1.3 versus 33 6 3, P , 0.03; TAU: 46.5 6 3.5 versus 81 6 2, P , 0.001), and tended to be even lower in patients who had not responded to chemotherapy or had relapsed within 18 mo of enrollment. Such changes were unrelated to age, sex, and WBC count. Changes in PFAA that occur in AML are only in part similar to those observed in solid tumors. The reduction of TAU appears to be a typical feature of AML and might be secondary to the deficiency of its precursors SER and MET. Further studies are under way aimed at clarifying whether PFAA might predict prognosis in AML, whether PFAA is normalized by remission induction, and if its correction may be of any benefit for patients with hematologic malignancies. Nutrition 1999;15:195–199. ©Elsevier Science Inc. 1999 Key words: amino acids, acute leukemia, taurine
INTRODUCTION
Tumor growth in both animals and humans is associated with a marked derangement in host metabolism.1,2 Via mechanisms probably involving peripheral cytokines,3 the tumor causes profound changes in protein metabolism (namely host nitrogen depletion, negative nitrogen balance,4 increased gluconeogenesis from amino acids,5,6 decreased muscle protein synthesis,7,8 and increased muscle protein breakdown8). As a result, protein turnover is increased during tumor growth.9 –11 In solid tumors, it has been shown that changes in protein metabolism result in modifications of the plasma-free amino acid (PFAA) profile.12 Consequently, plasma amino acid pattern may provide useful insights into the influence exerted by the tumor on the host’s protein metabolism, as well as on the selective need of specific amino acids for tumor protein synthesis.
It is known that human neoplasms originating in different organs may differ significantly from each other in terms of their rate of proliferation and influence on the host’s metabolism.13 Consequently, it is conceivable that biologically different tumors may cause different and specific changes in the host’s PFAA profile as a result of their peculiar influence on protein metabolism. Indeed, in a recent study in cancer-bearing patients, we have shown that different solid tumors exert different effects on PFAA.12 Despite several investigations describing the changes in PFAA in the presence of solid tumors,12, 14 –20 data on PFAA behavior in leukemic patients are surprisingly scanty.21–23 Therefore, we designed the present study to evaluate the PFAA profile in acute myeloid leukemic patients upon first diagnosis, to compare plasma amino acid profile in hematologic malignancies and solid tumors
Correspondence to: Filippo Rossi Fanelli, MD, Department Clinical Medicine, University “La Sapienza,” Viale dell’Universita` 37, 00185 Rome, Italy. E-mail: [email protected]
Nutrition 15:195–199, 1999 ©Elsevier Science Inc. 1999 Printed in the USA. All rights reserved.
0899-9007/99/$20.00 PII S0899-9007(98)00179-8
196
PLASMA AMINO ACIDS AND ACUTE LEUKEMIA TABLE I. PATIENT CHARACTERISTICS
Characteristic
Value
N Gender (M/F) Age (median/range) Subtype of leukemia M3/non-M3 Fasting serum glucose (mg/dL); mean 6 SE Serum creatinine (mg/dL); mean 6 SE White blood cell/cm2 (range) Lactate dehydrogenase (U/L); mean 6 SE
40 17/23 47.5/22–78 6/34 105.0 6 3.7 0.89 6 0.04 1080–276 500 548.0 6 143.6
and to evaluate whether the possibly detected changes in PFAA might have any relevance in the therapeutic approach to leukemic patients. MATERIALS AND METHODS
Patients and Controls The study was approved by the Local Ethics Committee. Forty consecutive patients (17 males, 23 females) with acute myeloid leukemia (AML) admitted to the Department of Hematology of the University of Rome “La Sapienza” were enrolled in the study. Patients were aged 22–78 y (median 47.5 y). All of them were enrolled upon first diagnosis of AML and had not been previously treated. Six patients had subtype M3 and 34 had non-M3 AML (2 patients, M1; 11 patients, M2; 7 patients, M4; 4 patients, M5; 2 patients, M6; 8 patients, others). The study was performed the day before the initiation of high-dose combined chemotherapy. In the AML group, white blood cells (WBC) count ranged from 1.08 to 276.5 3 103/cm2. All patients were considered well-nourished because none of them had lost less than 10% of usual body weight during the last 6 mo. Twenty-four healthy, well-nourished adult volunteers (12 males, 12 females) aged 21– 66 y (median 41 y) served as controls. Details of the patients are reported in Table I. Patients with diabetes, chronic renal failure, or concomitant neoplasm, conditions that are known to interfere with protein metabolism and to affect amino acid profile,2 were excluded from the study. Informed consent was obtained from both patients and controls for amino acid determinations. All subjects had been following a regular hospital diet during the 3 d before the study and were studied in the morning, after an overnight fast. All patients were followed up for 18 mo after enrollment in the study. According to their status 18 mo after chemotherapy for first remission induction, patients were subsequently subdivided into two groups: patients who had responded to chemotherapy and were in complete remission (CR) and patients who had not responded or had relapsed after chemotherapy for first remission induction (RR). Plasma Amino Acid Assay Free plasma amino acids were assayed by ion-exchange chromatography and postcolumn derivatization with ninhydrin as described elsewhere.14 Briefly, 10 mL of venous blood were drawn from an antecubital vein, collected into heparinized tubes and immediately centrifuged at 3000 rpm for 15 min. Thirty milligrams per milliliter of solid sulfosalicylic acid were then added to plasma for deproteinization. Samples were subsequently centrifuged at 4000 rpm for 20 min. The supernatant was then diluted
with a solution containing hydroxyproline as an internal standard, to reach a final concentration of 0.50 mmol/mL. An excellent separation of hydroxyproline is achieved by means of the method used. This aspect, coupled with the very low concentrations of hydroxyproline in human plasma (at the limit of detection with this method) makes hydroxyproline a suitable internal standard for plasma amino acid assay with this method. Samples were then filtered through Whatman No. 1 paper and stored at 270°C until use. One hundred microliters were analyzed in a Carlo Erba Automatic Amino Acid Analyzer (3A30), using lithium buffer to separate glutamine and asparagine. Plasma Tryptophan Assay Plasma total tryptophan (TTRP) was determined by using the spectrophotofluorimetric method described by Denckla and Dewey,24 as modified by Bloxam and Warren.25 The same procedure was used to estimate free tryptophan (FTRP) in an ultrafiltrate obtained from 2 mL plasma centrifuged at 800 g in an Amicon 224-CF-30 for 40 min at room temperature. All values were corrected for reagent blank. This method showed a recovery of 88%. Statistical Analysis Student’s t test for unpaired data and Spearman’s rank correlation were used for the statistical evaluation of the results. Data are expressed as mean 6 SE. RESULTS
Eighteen months after enrollment in the study, the status of the 40 enrolled patients was the following: 15 patients were alive (11 were disease-free, 3 had relapsed, 1 resistant to therapy); the remaining 25 patients had either died early during first remission induction (12 patients), or because of relapse or therapy-resistant disease (13 patients). Plasma amino acid concentrations in AML patients were, therefore, also examined by stratifying patients according to their response to therapy, in order to clarify whether changes in PFAA might be predictors of outcome in leukemic patients. Table II shows PFAA concentrations in control subjects (n 5 24), in the whole population of AML patients (n 5 40), in the 11 patients who had undergone complete remission (AML CR), and in the 17 patients with resistant disease or who had relapsed within 18 mo after chemotherapy (AML RR). Plasma concentrations of glutamic acid (GLU), glycine (GLY), ornithine (ORN), and free tryptophan (FTRP) were significantly higher in the 40 AML than in controls. Taurine (TAU), serine (SER), and methionine (MET) were significantly reduced when compared with controls. The concentrations of branched chain (valine, leucine, and isoleucine), aromatic (tyrosine, phenylalanine) amino acids, and total tryptophan did not differ between AML and controls. No gender-related differences in PFAA concentrations were observed among AML. Because it is known that M3 subtype AML has peculiar biological characteristics (manifested by its ability to induce disseminated intravascular coagulation), and differs from other AML subtypes in terms of therapeutic procedures used to induce remission, response to therapy, and prognosis, we looked at possible differences in PFAA between M3 and non-M3 AML patients. No differences in PFAA levels were observed between M3 patients (6) and non-M3 patients (34) with the exception of GLU, which was found to be significantly higher in non-M3 patients with respect to both M3 patients and controls (non-M3: 96.2 6 6.5 mmol/L versus M3: 56.2 6 9.0 and controls: 37 6 8, P , 0.01 and P , 0.001, respectively). GLU plasma concentrations were higher in M3 patients than in controls (56.2 6 9.0 versus 37 6 8), but this difference did not reach statistical significance.
PLASMA AMINO ACIDS AND ACUTE LEUKEMIA
197 TABLE II.
MEAN (6SEM) PLASMA AMINO ACID CONCENTRATIONS IN THE STUDY SUBJECTS Amino acid (mmol/L)
Controls (n 5 24)
AML All (n 5 40)
AML CR (n 5 11)
AML RR (n 5 17)
Aspartic acid Threonine Serine Glutamic acid Glutamine Proline Taurine Glycine Alanine Valine Methionine Isoleucine Leucine Tyrosine Phenylalanine Ornithine Lysine Histidine Arginine Citrulline Total tryptophan Free tryptophan
10.8 6 5.1 134 6 6 130 6 4 37 6 8 529 6 5 205 6 11 81 6 2 239 6 9 354 6 18 254 6 15 33 6 3 72 6 3 135 6 6 63 6 4 61 6 6 78 6 6 211 6 12 77 6 5 75 6 3 29 6 4 47.6 6 3.4 4.8 6 0.3
7.9 6 1.2 134.0 6 6.2 109.0 6 5.8* 90.2 6 6.1§ 555.6 6 18.0 197.5 6 9.9 46.5 6 3.5§ 295.0 6 14.8† 400.1 6 17.5 244.3 6 9.9 25.5 6 1.3 64.9 6 2.9 147.3 6 6.9 66.7 6 2.8 66.8 6 3.0 108.7 6 5.8§ 199.9 6 13.2 76.6 6 8.1 67.8 6 4.6 23.8 6 1.6 49.7 6 3.2 7.0 6 0.6‡
7.1 6 1.0 137.2 6 11.9 107.8 6 10.8* 88.8 6 11.1§ 564.4 6 39.1 210.7 6 20.0 43.5 6 3.6§ 320.4 6 33.1‡ 409.6 6 42.3 230.2 6 15.3 24.8 6 2.5 70.0 6 6.1 141.7 6 8.7 66.0 6 4.8 66.0 6 4.7 105.5 6 9.6§ 209.2 6 26.2 82.8 6 15.4 69.2 6 11.28 22.9 6 3.0 86.5 6 14.0 7.6 6 1.9‡
6.3 6 0.4§ 128.8 6 10.1 99.6 6 6.3§ 88.2 6 8.5§ 535.8 6 23.6 211.0 6 16.6 40.4 6 3.1§ 278.7 6 22.8 395.7 6 24.9 251.0 6 15.3 23.6 6 1.8* 71.4 6 4.1 147.3 6 11.5 65.6 6 4.4 63.0 6 5.5 106.3 6 5.6‡ 183.4 6 19.5 84.7 6 15.4 63.6 6 6.2 23.2 6 1.9 65.0 6 6.6 7.3 6 0.7‡
Significance versus controls: * P , 0.03. † P , 0.01. ‡ P , 0.005. § P , 0.001. AML All, acute myeloid leukemia; CR, complete remission; RR, resistant disease or patients who relapsed within 18 mo after chemotherapy.
Plasma concentrations of GLU, FTRP, ORN, GLY (which were higher than in controls) and of SER, MET, and TAU (which were lower than in controls) did not correlate with either WBC or lactate dehydrogenase (LDH) activity. When results were examined by stratifying patients according to the response to therapy, the concentrations of those amino acids that resulted in increases with respect to controls at diagnosis (GLU, FTRP, ORN, and GLY) were similar in AML CR and in AML RR group (Table II). However, TAU, SER, and MET tended to be lower, although not significantly, in AML RR patients (17 patients) with respect to AML CR patients (11 patients) (see Table II). Patients in the AML CR and in the AML RR groups were equally distributed as for induction remission protocol. DISCUSSION
The data obtained in the present study confirm that in adult well-nourished patients with AML, the plasma amino acid pattern is altered with respect to normal subjects, suggesting that hematologic malignancies may indeed affect host protein metabolism. The rise of glutamic acid and ornithine might be the result of altered nitrogen utilization: tumor burden might act as a “nitrogen trap” actively competing with the host for nitrogen compounds because of the need of the amino groups for its own protein synthesis.26 Animal data would support this observation because glutamic acid normalizes once the tumor is removed.27 The increase in glutamic acid plasma concentrations is in keeping with previous studies21,22 in leukemic patients and with our previous
reports in patients bearing solid tumors,12,14 thus suggesting that the rise of this amino acid may represent a common feature of neoplastic disease. Plasma GLU concentrations were significantly higher in non-M3 than in M3 patients; however, the small number of patients in the M3 group prevents us from drawing definite conclusions about this aspect. The rise in FTRP confirms previous reports from our group12,14,28,29 showing that increased plasma levels of FTRP are frequently found in the presence of neoplastic disease. These findings, together with the previously reported data indicating that surgical removal of the tumor in humans is followed by a normalization of plasma FTRP concentrations,30 suggest that this amino acid might be utilized as a marker of tumor presence. The mechanism(s) by which tumors may induce an increase in the unbound quota of tryptophan in both humans and animals29,31 is not yet clear. However, animal studies suggest a role for circulating cytokines.32 Increased plasma FTRP concentrations have been associated with anorexia and reduced food intake in patients with chronic diseases including cancer.33 Interestingly, none of the leukemic patients included in the present investigation reported a reduction in appetite or in food intake, or both (data not shown), despite increased FTRP plasma concentrations. This finding would suggest that cancer anorexia might be mediated by factors other than only FTRP. Of particular interest in this clinical setting is the significant reduction of SER, MET, and TAU, the changes of which might be interrelated. It is known that in adult mammalians, TAU may be
198
PLASMA AMINO ACIDS AND ACUTE LEUKEMIA
synthesized through different metabolic pathways using mainly MET,34 but also SER as precursor amino acid.35 MET is essential in the methylation process in DNA and RNA synthesis.36 –38 Although the reasons for SER reduction are not entirely clear, MET in leukemic patients could be reduced because of abnormalities in cellular DNA synthesis. Both SER and MET deficiency, however, might eventually result in a reduction in plasma TAU. In the present study, TAU and its precursor amino acids, SER and MET, were consistently reduced. In fact, 37 of 40 leukemic patients (92%) showed TAU concentrations lower than in control subjects, whereas 27 of 40 (67%) also showed reduced SER and MET plasma concentrations. Although we did not measure cysteine, the intermediate precursor for TAU synthesis from MET,34 it is conceivable that this amino acid would be also reduced in AML. It cannot be excluded, however, that TAU deficiency in leukemic patients might also be secondary to a reduction in the activity of the enzyme cysteine sulfinate decarboxylase, which is thought to be the rate-limiting step in TAU synthesis.34 Whatever the cause of TAU reduction, however, the present data would indicate that in leukemic patients, TAU endogenous synthesis from precursors is insufficient to maintain normal plasma TAU concentrations. TAU reduction might have some relevance in the clinical outcome of AML. This suggestion is based on experimental and clinical evidence indicating that TAU is the most abundant intracellular free amino acid in WBC.39 Plasma concentrations of this amino acid drop significantly after chemotherapy for hematologic
malignancies40 and its intracellular content was demonstrated to correlate directly to the chemosensitivity of the leukemia cell line.41 In addition, TAU supplementation has been shown to accelerate recovery from neutropenia in irradiated mice.42 This acceleration is likely the consequence of its effect as a membrane stabilizer and antioxidant agent.43 The current findings that patients with poorer outcome tend to have lower plasma concentrations of TAU and its precursors, may favor the assumption that TAU deficiency might be detrimental in acute leukemic patients. Further in vitro and in vivo studies should help clarify whether the plasma amino acid profile in leukemic patients is at least in part normalized by induction remission and whether plasma amino acid imbalance reoccurs during relapse and, therefore, whether changes in PFAA may be predictors of prognosis in AML. Moreover, it remains to be elucidated if TAU deficiency is common to other hematologic malignancies and if its supplementation may be of any benefit during or after chemotherapy for acute leukemias and other non-hematologic malignancies, as well as for other clinical conditions, as recently proposed.44 In summary, the presence of AML is associated with changes in the PFAA profile that are only in part similar to those observed in the presence of solid tumors (i.e., the increase of GLU, ORN, and FTRP). The reduction of TAU appears to be a typical feature of acute myeloid leukemias and might be secondary to the deficiency of its biosynthetic precursors. The value of some PFAA alteration in predicting prognosis of AML warrants further investigation.
REFERENCES 1. Heber D, Byerey LO, Chlebowski RT. Metabolic abnormalities in the cancer patients. Cancer 1985;5:225 2. Rossi Fanelli F, Cangiano C, Muscaritoli M, et al. Tumor-induced changes in host metabolism: a possible marker of neoplastic disease. Nutrition 1995;11(suppl):595 3. Langstein HN, Norton JA. Mechanisms of cancer anorexia. Hematol Oncol Clin North Am 1991;5:103 4. Brennan MF, Burt ME. Nitrogen metabolism in cancer patients. Cancer Treat Rep 1981;65:67 5. Gold J. Cancer cachexia and gluconeogenesis. Ann NY Acad Sci 1974;230:103 6. Waterhouse C, Jeanpretre N, Keilson J. Gluconeogenesis from alanine in patients with progressive malignant disease. Cancer Res 1979;39: 1968 7. Lundholm K, Edstrom S, Ekman L. A comparative study of the influence of malignant tumor on host metabolism in mice and man. Cancer 1978;42:453 8. Norton JA, Shamberger R, Stein TP, Milne GWA, Brennan MF. The influence of tumor-bearing on protein metabolism in the rat. J Surg Res 1981;30:456 9. Carmichael MJ, Clague MB, Keir MH, Johnston IA. Whole body protein turnover, synthesis and breakdown in patients with colorectal carcinoma. Br J Surg 1980;67:736 10. Eden E, Ekman L, Bennegard K, Lindmark L, Lundholm K. Wholebody tyrosine flux in relation to energy expenditure in weight-losing cancer patients. Metabolism 1984;33:1020 11. Jeevanandam M, Horowitz GD, Lowry SF, Brennan MF. Cancer cachexia and protein metabolism. Lancet 1984;1:1423 12. Cascino A, Muscaritoli M, Cangiano C, et al. Plasma amino acid imbalance in patients with lung and breast cancer. Anticancer Res 1995;15:507 13. Kern KA, Norton JA. Cancer cachexia. JPEN 1988;12:286 14. Cascino A, Cangiano C, Ceci F, et al. Plasma amino acids in human cancer: the individual role of tumour, malnutrition and glucose tolerance. Clin Nutr 1988;7:213 15. Clarke EF, Lewis AM, Waterhouse C. Peripheral amino acid levels in patients with cancer. Cancer 1979;42:2909 16. Ching N, Grossi C, Jham G, et al. Plasma amino acid and serum unesterified fatty acid deficits and the effect of nutritional support in chemotherapy treatment. Surgery 1984;95:730
17. Norton JA, Gorschboth CM, Wesley RA, Burt ME, Brennan MF. Fasting plasma amino acid levels in cancer patients. Cancer 1985;56: 1181 18. Watanabe A, Higashi T, Sakata T, et al. Serum amino acid levels in patients with hepatocellular carcinoma. Cancer 1984;54:1875 19. Naini AB, Dickerson JWT, Brown MM. Preoperative and postoperative levels of plasma protein and amino acid in esophageal and lung cancer patients. Cancer 1988;62:355 20. Kubota A, Meguid MM, Hitch D. Amino acid profiles correlate diagnostically with organ site in three kinds of malignant tumors. Cancer 1992;69:2343 21. Waisman HA, Pastel RA, Poncher HG. Amino acid metabolism in patients with acute leukemia. Pediatrics 1952;10:653 22. Kelley JJ, Waisman HA. Quantitative plasma amino acid values in leukemic blood. Blood 1957;12:635 23. Rudman D, Vogler WR, Howard CH, Gerron GG. Observations on the plasma amino acids of patients with acute leukemia. Cancer Res 1971;31:1159 24. Denckla WD, Dewey HK. The determination of tryptophan in plasma, liver, and urine. J Lab Clin Med 1967;69:160 25. Bloxam DL, Warren WH. Error in the determination of tryptophan by the method of Denckla and Dewey. A revised procedure. Anal Biochem 1974;60:621 26. Landel AM, Hammond WG, Meguid MM. Aspects of amino acids and protein metabolism in cancer bearing states. Cancer 1985;55:230 27. Landel AM, Lo C-C, Meguid MM, Rivera D. Effect of methylcholanthrene-induced sarcoma and its removal on rat plasma and intracellular free amino acid content. Surg Res Commun 1987;1:273 28. Rossi Fanelli F, Cangiano C, Ceci F, et al. Plasma tryptophan and anorexia in human cancer. Eur J Cancer Clin Oncol 1986;22:89 29. Meguid MM, Muscaritoli M, Beverly JL, et al. The early cancer anorexia paradigm: changes in plasma free tryptophan and feeding indexes. JPEN 1992;16 (suppl):56S 30. Cascino A, Cangiano C, Ceci F, et al. Increased plasma free tryptophan levels in human cancer: a tumor related effect? Anticancer Res 1991;11:1313 31. Muscaritoli M, Meguid MM, Beverly JL, et al. Mechanism of early tumor anorexia. J Surg Res 1996;60:388 32. Dunn AJ. Endotoxin-induced activation of cerebral catecholamine and
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33. 34. 35. 36.
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serotonin metabolism: comparison with interleukin-1. J Pharmacol Exp Ther 1992;261:964 Rossi Fanelli F, Cangiano C. Increased availability of tryptophan in brain as common pathogenic mechanism for anorexia associated with different diseases. Nutrition 1991;7:364 Huxtable RJ. Physiological action of taurine. Physiol Rev 1992;72: 101 Wright CE, Tallan HH, Lin YY. Taurine: biological update. Ann Rev Biochem 1986;55:427 Ashe H, Clar BR, Hardy DN, et al. N-Methyltetrahydrofolate: homocysteine methyl-transferase activity in extracts from normal, malignant and embryonic tissue culture cells. Biochem Biophys Res Commun 1974;T57:417 Chello PL, Bertino JR. Effect of methionine deprivation on L5178 murine leukemia cells in culture. Interference with the antineoplastic effect of methotrexate. Biochem Pharmacol 1976;25:889 Hoffman RM, Jacobsen SJ, Erbe RW. Reversion to methionine inde-
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pendence by malignant rat and SV40-transformed human fibroblast. Biochem Biophys Res Commun 1978;82:228 Fukuda K, Hirai Y, Yoshida H, Nakajima T, Usai T. Free amino acid content of lymphocytes and granulocytes compared. Clin Chem 1982; 28:1758 Desai TK, Maliakal J, Kinsie JL, et al. Taurine deficiency after intensive chemotherapy and/or radiation. Am J Clin Nutr 1992;55:708 Jiang XR, Yang M, Morris CJ, et al. High field proton NMR investigations on the metabolic profiles of multidrug-sensitive and -resistant leukaemic cell lines: evidence for diminished taurine levels in multidrug-resistant cells. Free Rad Res Commun 1993;19:355 Abe M, Takahashi M, Takeuchi K, Fukuda M. Studies on the significance of taurine in radiation injury. Radiation Res 1978;33:563 Hayes KC, Carey RE, Schmidt SY. Retinal degeneration associated with taurine deficiency in the cat. Science 1975;188:949 Stapleton PP, Charles RP, Redmond HP, Boucher-Hayes DJ. Taurine and human nutrition. Clin Nutr 1997;16:103
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CONFERENCE REVIEW Sixth Annual Congress on Women’s Health
Nutrition Vol. 15, No. 3, 1999
Plasma Amino Acid Concentrations in Patients With Acute Myelogenous Leukemia M. MUSCARITOLI, MD, L. CONVERSANO, MD, M. C. PETTI, MD, A. CASCINO, MD, S. MECAROCCI, MD, M. A. ANNICCHIARICO, MD, AND F. ROSSI FANELLI, MD From the Departments of Clinical Medicine and Human Biopathology, Hematology, University “La Sapienza,” Rome, Italy Date accepted: 11 May 1998 ABSTRACT
Changes in plasma-free amino acid (PFAA) concentrations in the presence of solid tumors have been widely described. Conversely, the PFAA profile in patients with acute leukemias is less well defined. The aim of the present study was to clarify whether the PFAA profile is altered in patients with acute myeloid leukemia (AML), whether the profile differs from the PFAA profile of solid tumors, and whether it may predict outcome of AML. Fasting PFAA were measured in 40 untreated, normally nourished patients with AML (17 males, 23 females), ages 22–78 y, with white blood cell (WBC) counts ranging from 1.08 to 276.5 3 103/cm2, and in 24 healthy volunteers. Plasma concentrations (mmol/L, mean 6 SE) of glutamic acid (GLU), free tryptophan (FTRP), ornithine (ORN), and glycine (GLY) were significantly higher in AML (GLU: 90.2 6 6.1 versus 37 6 8; FTRP: 7.0 6 0.6 versus 4.8 6 0.3, P , 0.005; ORN: 108.7 6 5.8 versus 78 6 6, P , 0.001; GLY: 295.0 6 14.8 versus 239 6 9, P , 0.01), whereas serine (SER), methionine (MET), and taurine (TAU) were significantly lower in AML than in controls (SER: 109.0 6 5.8 versus 130 6 4, P , 0.03; MET: 25.5 6 1.3 versus 33 6 3, P , 0.03; TAU: 46.5 6 3.5 versus 81 6 2, P , 0.001), and tended to be even lower in patients who had not responded to chemotherapy or had relapsed within 18 mo of enrollment. Such changes were unrelated to age, sex, and WBC count. Changes in PFAA that occur in AML are only in part similar to those observed in solid tumors. The reduction of TAU appears to be a typical feature of AML and might be secondary to the deficiency of its precursors SER and MET. Further studies are under way aimed at clarifying whether PFAA might predict prognosis in AML, whether PFAA is normalized by remission induction, and if its correction may be of any benefit for patients with hematologic malignancies. Nutrition 1999;15:195–199. ©Elsevier Science Inc. 1999 Key words: amino acids, acute leukemia, taurine
INTRODUCTION
Tumor growth in both animals and humans is associated with a marked derangement in host metabolism.1,2 Via mechanisms probably involving peripheral cytokines,3 the tumor causes profound changes in protein metabolism (namely host nitrogen depletion, negative nitrogen balance,4 increased gluconeogenesis from amino acids,5,6 decreased muscle protein synthesis,7,8 and increased muscle protein breakdown8). As a result, protein turnover is increased during tumor growth.9 –11 In solid tumors, it has been shown that changes in protein metabolism result in modifications of the plasma-free amino acid (PFAA) profile.12 Consequently, plasma amino acid pattern may provide useful insights into the influence exerted by the tumor on the host’s protein metabolism, as well as on the selective need of specific amino acids for tumor protein synthesis.
It is known that human neoplasms originating in different organs may differ significantly from each other in terms of their rate of proliferation and influence on the host’s metabolism.13 Consequently, it is conceivable that biologically different tumors may cause different and specific changes in the host’s PFAA profile as a result of their peculiar influence on protein metabolism. Indeed, in a recent study in cancer-bearing patients, we have shown that different solid tumors exert different effects on PFAA.12 Despite several investigations describing the changes in PFAA in the presence of solid tumors,12, 14 –20 data on PFAA behavior in leukemic patients are surprisingly scanty.21–23 Therefore, we designed the present study to evaluate the PFAA profile in acute myeloid leukemic patients upon first diagnosis, to compare plasma amino acid profile in hematologic malignancies and solid tumors
Correspondence to: Filippo Rossi Fanelli, MD, Department Clinical Medicine, University “La Sapienza,” Viale dell’Universita` 37, 00185 Rome, Italy. E-mail: [email protected]
Nutrition 15:195–199, 1999 ©Elsevier Science Inc. 1999 Printed in the USA. All rights reserved.
0899-9007/99/$20.00 PII S0899-9007(98)00179-8
196
PLASMA AMINO ACIDS AND ACUTE LEUKEMIA TABLE I. PATIENT CHARACTERISTICS
Characteristic
Value
N Gender (M/F) Age (median/range) Subtype of leukemia M3/non-M3 Fasting serum glucose (mg/dL); mean 6 SE Serum creatinine (mg/dL); mean 6 SE White blood cell/cm2 (range) Lactate dehydrogenase (U/L); mean 6 SE
40 17/23 47.5/22–78 6/34 105.0 6 3.7 0.89 6 0.04 1080–276 500 548.0 6 143.6
and to evaluate whether the possibly detected changes in PFAA might have any relevance in the therapeutic approach to leukemic patients. MATERIALS AND METHODS
Patients and Controls The study was approved by the Local Ethics Committee. Forty consecutive patients (17 males, 23 females) with acute myeloid leukemia (AML) admitted to the Department of Hematology of the University of Rome “La Sapienza” were enrolled in the study. Patients were aged 22–78 y (median 47.5 y). All of them were enrolled upon first diagnosis of AML and had not been previously treated. Six patients had subtype M3 and 34 had non-M3 AML (2 patients, M1; 11 patients, M2; 7 patients, M4; 4 patients, M5; 2 patients, M6; 8 patients, others). The study was performed the day before the initiation of high-dose combined chemotherapy. In the AML group, white blood cells (WBC) count ranged from 1.08 to 276.5 3 103/cm2. All patients were considered well-nourished because none of them had lost less than 10% of usual body weight during the last 6 mo. Twenty-four healthy, well-nourished adult volunteers (12 males, 12 females) aged 21– 66 y (median 41 y) served as controls. Details of the patients are reported in Table I. Patients with diabetes, chronic renal failure, or concomitant neoplasm, conditions that are known to interfere with protein metabolism and to affect amino acid profile,2 were excluded from the study. Informed consent was obtained from both patients and controls for amino acid determinations. All subjects had been following a regular hospital diet during the 3 d before the study and were studied in the morning, after an overnight fast. All patients were followed up for 18 mo after enrollment in the study. According to their status 18 mo after chemotherapy for first remission induction, patients were subsequently subdivided into two groups: patients who had responded to chemotherapy and were in complete remission (CR) and patients who had not responded or had relapsed after chemotherapy for first remission induction (RR). Plasma Amino Acid Assay Free plasma amino acids were assayed by ion-exchange chromatography and postcolumn derivatization with ninhydrin as described elsewhere.14 Briefly, 10 mL of venous blood were drawn from an antecubital vein, collected into heparinized tubes and immediately centrifuged at 3000 rpm for 15 min. Thirty milligrams per milliliter of solid sulfosalicylic acid were then added to plasma for deproteinization. Samples were subsequently centrifuged at 4000 rpm for 20 min. The supernatant was then diluted
with a solution containing hydroxyproline as an internal standard, to reach a final concentration of 0.50 mmol/mL. An excellent separation of hydroxyproline is achieved by means of the method used. This aspect, coupled with the very low concentrations of hydroxyproline in human plasma (at the limit of detection with this method) makes hydroxyproline a suitable internal standard for plasma amino acid assay with this method. Samples were then filtered through Whatman No. 1 paper and stored at 270°C until use. One hundred microliters were analyzed in a Carlo Erba Automatic Amino Acid Analyzer (3A30), using lithium buffer to separate glutamine and asparagine. Plasma Tryptophan Assay Plasma total tryptophan (TTRP) was determined by using the spectrophotofluorimetric method described by Denckla and Dewey,24 as modified by Bloxam and Warren.25 The same procedure was used to estimate free tryptophan (FTRP) in an ultrafiltrate obtained from 2 mL plasma centrifuged at 800 g in an Amicon 224-CF-30 for 40 min at room temperature. All values were corrected for reagent blank. This method showed a recovery of 88%. Statistical Analysis Student’s t test for unpaired data and Spearman’s rank correlation were used for the statistical evaluation of the results. Data are expressed as mean 6 SE. RESULTS
Eighteen months after enrollment in the study, the status of the 40 enrolled patients was the following: 15 patients were alive (11 were disease-free, 3 had relapsed, 1 resistant to therapy); the remaining 25 patients had either died early during first remission induction (12 patients), or because of relapse or therapy-resistant disease (13 patients). Plasma amino acid concentrations in AML patients were, therefore, also examined by stratifying patients according to their response to therapy, in order to clarify whether changes in PFAA might be predictors of outcome in leukemic patients. Table II shows PFAA concentrations in control subjects (n 5 24), in the whole population of AML patients (n 5 40), in the 11 patients who had undergone complete remission (AML CR), and in the 17 patients with resistant disease or who had relapsed within 18 mo after chemotherapy (AML RR). Plasma concentrations of glutamic acid (GLU), glycine (GLY), ornithine (ORN), and free tryptophan (FTRP) were significantly higher in the 40 AML than in controls. Taurine (TAU), serine (SER), and methionine (MET) were significantly reduced when compared with controls. The concentrations of branched chain (valine, leucine, and isoleucine), aromatic (tyrosine, phenylalanine) amino acids, and total tryptophan did not differ between AML and controls. No gender-related differences in PFAA concentrations were observed among AML. Because it is known that M3 subtype AML has peculiar biological characteristics (manifested by its ability to induce disseminated intravascular coagulation), and differs from other AML subtypes in terms of therapeutic procedures used to induce remission, response to therapy, and prognosis, we looked at possible differences in PFAA between M3 and non-M3 AML patients. No differences in PFAA levels were observed between M3 patients (6) and non-M3 patients (34) with the exception of GLU, which was found to be significantly higher in non-M3 patients with respect to both M3 patients and controls (non-M3: 96.2 6 6.5 mmol/L versus M3: 56.2 6 9.0 and controls: 37 6 8, P , 0.01 and P , 0.001, respectively). GLU plasma concentrations were higher in M3 patients than in controls (56.2 6 9.0 versus 37 6 8), but this difference did not reach statistical significance.
PLASMA AMINO ACIDS AND ACUTE LEUKEMIA
197 TABLE II.
MEAN (6SEM) PLASMA AMINO ACID CONCENTRATIONS IN THE STUDY SUBJECTS Amino acid (mmol/L)
Controls (n 5 24)
AML All (n 5 40)
AML CR (n 5 11)
AML RR (n 5 17)
Aspartic acid Threonine Serine Glutamic acid Glutamine Proline Taurine Glycine Alanine Valine Methionine Isoleucine Leucine Tyrosine Phenylalanine Ornithine Lysine Histidine Arginine Citrulline Total tryptophan Free tryptophan
10.8 6 5.1 134 6 6 130 6 4 37 6 8 529 6 5 205 6 11 81 6 2 239 6 9 354 6 18 254 6 15 33 6 3 72 6 3 135 6 6 63 6 4 61 6 6 78 6 6 211 6 12 77 6 5 75 6 3 29 6 4 47.6 6 3.4 4.8 6 0.3
7.9 6 1.2 134.0 6 6.2 109.0 6 5.8* 90.2 6 6.1§ 555.6 6 18.0 197.5 6 9.9 46.5 6 3.5§ 295.0 6 14.8† 400.1 6 17.5 244.3 6 9.9 25.5 6 1.3 64.9 6 2.9 147.3 6 6.9 66.7 6 2.8 66.8 6 3.0 108.7 6 5.8§ 199.9 6 13.2 76.6 6 8.1 67.8 6 4.6 23.8 6 1.6 49.7 6 3.2 7.0 6 0.6‡
7.1 6 1.0 137.2 6 11.9 107.8 6 10.8* 88.8 6 11.1§ 564.4 6 39.1 210.7 6 20.0 43.5 6 3.6§ 320.4 6 33.1‡ 409.6 6 42.3 230.2 6 15.3 24.8 6 2.5 70.0 6 6.1 141.7 6 8.7 66.0 6 4.8 66.0 6 4.7 105.5 6 9.6§ 209.2 6 26.2 82.8 6 15.4 69.2 6 11.28 22.9 6 3.0 86.5 6 14.0 7.6 6 1.9‡
6.3 6 0.4§ 128.8 6 10.1 99.6 6 6.3§ 88.2 6 8.5§ 535.8 6 23.6 211.0 6 16.6 40.4 6 3.1§ 278.7 6 22.8 395.7 6 24.9 251.0 6 15.3 23.6 6 1.8* 71.4 6 4.1 147.3 6 11.5 65.6 6 4.4 63.0 6 5.5 106.3 6 5.6‡ 183.4 6 19.5 84.7 6 15.4 63.6 6 6.2 23.2 6 1.9 65.0 6 6.6 7.3 6 0.7‡
Significance versus controls: * P , 0.03. † P , 0.01. ‡ P , 0.005. § P , 0.001. AML All, acute myeloid leukemia; CR, complete remission; RR, resistant disease or patients who relapsed within 18 mo after chemotherapy.
Plasma concentrations of GLU, FTRP, ORN, GLY (which were higher than in controls) and of SER, MET, and TAU (which were lower than in controls) did not correlate with either WBC or lactate dehydrogenase (LDH) activity. When results were examined by stratifying patients according to the response to therapy, the concentrations of those amino acids that resulted in increases with respect to controls at diagnosis (GLU, FTRP, ORN, and GLY) were similar in AML CR and in AML RR group (Table II). However, TAU, SER, and MET tended to be lower, although not significantly, in AML RR patients (17 patients) with respect to AML CR patients (11 patients) (see Table II). Patients in the AML CR and in the AML RR groups were equally distributed as for induction remission protocol. DISCUSSION
The data obtained in the present study confirm that in adult well-nourished patients with AML, the plasma amino acid pattern is altered with respect to normal subjects, suggesting that hematologic malignancies may indeed affect host protein metabolism. The rise of glutamic acid and ornithine might be the result of altered nitrogen utilization: tumor burden might act as a “nitrogen trap” actively competing with the host for nitrogen compounds because of the need of the amino groups for its own protein synthesis.26 Animal data would support this observation because glutamic acid normalizes once the tumor is removed.27 The increase in glutamic acid plasma concentrations is in keeping with previous studies21,22 in leukemic patients and with our previous
reports in patients bearing solid tumors,12,14 thus suggesting that the rise of this amino acid may represent a common feature of neoplastic disease. Plasma GLU concentrations were significantly higher in non-M3 than in M3 patients; however, the small number of patients in the M3 group prevents us from drawing definite conclusions about this aspect. The rise in FTRP confirms previous reports from our group12,14,28,29 showing that increased plasma levels of FTRP are frequently found in the presence of neoplastic disease. These findings, together with the previously reported data indicating that surgical removal of the tumor in humans is followed by a normalization of plasma FTRP concentrations,30 suggest that this amino acid might be utilized as a marker of tumor presence. The mechanism(s) by which tumors may induce an increase in the unbound quota of tryptophan in both humans and animals29,31 is not yet clear. However, animal studies suggest a role for circulating cytokines.32 Increased plasma FTRP concentrations have been associated with anorexia and reduced food intake in patients with chronic diseases including cancer.33 Interestingly, none of the leukemic patients included in the present investigation reported a reduction in appetite or in food intake, or both (data not shown), despite increased FTRP plasma concentrations. This finding would suggest that cancer anorexia might be mediated by factors other than only FTRP. Of particular interest in this clinical setting is the significant reduction of SER, MET, and TAU, the changes of which might be interrelated. It is known that in adult mammalians, TAU may be
198
PLASMA AMINO ACIDS AND ACUTE LEUKEMIA
synthesized through different metabolic pathways using mainly MET,34 but also SER as precursor amino acid.35 MET is essential in the methylation process in DNA and RNA synthesis.36 –38 Although the reasons for SER reduction are not entirely clear, MET in leukemic patients could be reduced because of abnormalities in cellular DNA synthesis. Both SER and MET deficiency, however, might eventually result in a reduction in plasma TAU. In the present study, TAU and its precursor amino acids, SER and MET, were consistently reduced. In fact, 37 of 40 leukemic patients (92%) showed TAU concentrations lower than in control subjects, whereas 27 of 40 (67%) also showed reduced SER and MET plasma concentrations. Although we did not measure cysteine, the intermediate precursor for TAU synthesis from MET,34 it is conceivable that this amino acid would be also reduced in AML. It cannot be excluded, however, that TAU deficiency in leukemic patients might also be secondary to a reduction in the activity of the enzyme cysteine sulfinate decarboxylase, which is thought to be the rate-limiting step in TAU synthesis.34 Whatever the cause of TAU reduction, however, the present data would indicate that in leukemic patients, TAU endogenous synthesis from precursors is insufficient to maintain normal plasma TAU concentrations. TAU reduction might have some relevance in the clinical outcome of AML. This suggestion is based on experimental and clinical evidence indicating that TAU is the most abundant intracellular free amino acid in WBC.39 Plasma concentrations of this amino acid drop significantly after chemotherapy for hematologic
malignancies40 and its intracellular content was demonstrated to correlate directly to the chemosensitivity of the leukemia cell line.41 In addition, TAU supplementation has been shown to accelerate recovery from neutropenia in irradiated mice.42 This acceleration is likely the consequence of its effect as a membrane stabilizer and antioxidant agent.43 The current findings that patients with poorer outcome tend to have lower plasma concentrations of TAU and its precursors, may favor the assumption that TAU deficiency might be detrimental in acute leukemic patients. Further in vitro and in vivo studies should help clarify whether the plasma amino acid profile in leukemic patients is at least in part normalized by induction remission and whether plasma amino acid imbalance reoccurs during relapse and, therefore, whether changes in PFAA may be predictors of prognosis in AML. Moreover, it remains to be elucidated if TAU deficiency is common to other hematologic malignancies and if its supplementation may be of any benefit during or after chemotherapy for acute leukemias and other non-hematologic malignancies, as well as for other clinical conditions, as recently proposed.44 In summary, the presence of AML is associated with changes in the PFAA profile that are only in part similar to those observed in the presence of solid tumors (i.e., the increase of GLU, ORN, and FTRP). The reduction of TAU appears to be a typical feature of acute myeloid leukemias and might be secondary to the deficiency of its biosynthetic precursors. The value of some PFAA alteration in predicting prognosis of AML warrants further investigation.
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