Clinical Cancer Research Vol. 11, 2986-2990, April 15, 2005
© 2005 American Association for Cancer Research
Imaging, Diagnosis, Prognosis |
N1,N12-Diacetylspermine as a Sensitive and Specific Novel Marker for Early- and Late-Stage Colorectal and Breast Cancers
Kyoko Hiramatsu1,
Keiichi Takahashi2,
Taturo Yamaguchi2,
Hiroshi Matsumoto2,
Hidenori Miyamoto2,
Souichi Tanaka5,
Chikako Tanaka2,
Yoshiko Tamamori3,
Mari Imajo6,
Masashi Kawaguchi6,
Masakazu Toi2,
Takeo Mori4 and
Masao Kawakita6
Authors' Affiliations: 1 Medical Research and Development Center, Tokyo Metropolitan Institute of Medical Science, 2 Department of Surgery, 3 Clinical Laboratory, 4 Tokyo Metropolitan Komagome Hospital, 5 Department of Surgery, Tokyo Metropolitan Bokutou Hospital, and 6 Department of Applied Chemistry, Kogakuin University
Requests for reprints: Masao Kawakita, Department of Applied Chemistry, Kogakuin University, 1-24-2 Nishi-shinjuku, Shinjuku-ku, Tokyo 163-8677, Japan. Phone: 81-3-33402731; Fax: 81-3-33400147; E-mail: bt13004{at}ns.kogakuin.ac.jp.
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Abstract
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Purpose: N1,N12-diacetylspermine (DiAcSpm) in the urine of colorectal and breast cancer patients was examined to establish its usefulness as a novel diagnostic tool for detecting these cancers at clinically early stages.
Experimental Design: Urine samples from 248 colon cancer patients and 83 breast cancer patients as well as 51 patients with benign gastrointestinal diseases treated in Tokyo Metropolitan Komagome Hospital during the period of August 1999 to January 2004 were collected. DiAcSpm was analyzed by ELISA and its sensitivity for malignant conditions was compared with that of serum carcinoembryonic antigen (CEA), CA19-9, and CA15-3.
Results: The sensitivity of urinary DiAcSpm for colon cancer patients (n = 248) was 75.8% (mean ± 2 SD for 52 healthy controls as a cutoff value), which was markedly higher than the sensitivities of serum CEA (39.5%, P < 0.0001) and CA19-9 (14.1%, P < 0.0001). DiAcSpm was elevated in 60% of tumor-node-metastasis cancer stage 0 + I patients, whereas only 10% (P < 0.0001) and 5% (P < 0.0001) of these patients were CEA- and CA19-9–positive, respectively. The sensitivity of urinary DiAcSpm for 83 cases of breast cancer (60.2%) was higher than the sensitivities of CEA (37.3%, P = 0.0032) and CA15-3 (37.3%, P = 0.0032). DiAcSpm was elevated in 28% of tumor-node-metastasis stage I + II patients, whereas only 3% (P = 0.0064) and 0% (P = 0.001) of these patients were CEA- and CA15-3–positive, respectively.
Conclusion: The observations indicate that urinary DiAcSpm is a more sensitive marker than CEA, CA19-9, and CA15-3 and that it can efficiently detect colorectal and breast cancers at early stages.
Key Words: Gastrointestinal cancers: colorectal • Breast cancer • Tumor markers and detection of metastasis • CLINICAL RESEARCH
We reported previously that N1,N12-diacetylspermine (DiAcSpm) is excreted in the urine of healthy persons, with small individual variations in the amount (1). We devised a high-performance liquid chromatography separation system connected to an in-line enzymatic detection system for DiAcSpm and carried out precise analyses of urinary DiAcSpm in healthy persons as well as patients with malignant diseases.
Our analysis revealed that DiAcSpm may be useful as a novel diagnostic and prognostic tumor marker in that its excretion in urine is elevated significantly and frequently in patients with urogenital malignancies and tends to recover to the normal level on remission (2, 3). At the same time, we noted that monoacetylpolyamines that constitute a major part of urinary polyamines, including N-acetylputrescine, N1-acetylspermidine, and N8-acetylspermidine, were much less sensitive as markers for these urogenital malignancies than DiAcSpm and could not be considered practical tumor markers. The part of our observations concerning conventional monoacetylpolyamines was very well in accord with the popular evaluation of urinary polyamines at that time (4), but our results on DiAcSpm analysis were radically different from those on other polyamine derivatives and looked highly promising (2, 3).
Although the biochemistry and clinical chemistry of DiAcSpm remain largely obscure at present because of the lack of intensive studies of its metabolism, it is quite reasonable that various cancers might excrete increased amounts of DiAcSpm, because polyamine metabolism is activated in association with various types of cell proliferation (5). In this study, we examined the excretion of DiAcSpm in the urine of colon and breast cancer patients and compared the urinary DiAcSpm level with serum levels of other established tumor markers, including carcinoembryonic antigen (CEA), CA19-9, and CA15-3. Our analysis revealed that DiAcSpm is a more sensitive marker than these established markers for colon and breast cancers and that it can efficiently detect cancers at early clinical stages.
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Materials and Methods
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Urine samples from 248 colon cancer patients and 83 breast cancer patients treated at the Tokyo Metropolitan Komagome Hospital during the period of August 1999 to January 2004 were collected and analyzed for DiAcSpm. Serum CEA, CA19-9, and CA15-3 levels were determined for these patients at the Clinical Laboratory of the Tokyo Metropolitan Komagome Hospital. Urine samples were also collected from 51 patients with the following benign gastrointestinal diseases (with the number of cases in parentheses; also see Table 1): benign tumors, including adenoma (n = 15), carcinoid (n = 2), neurilemoma (n = 1), and lipoma (n = 1); inflammatory bowel diseases, including ulcerative colitis (n = 4), Crohn's disease (n = 2), and radiation enterocolitis (n = 1); acute inflammatory diseases, including cholecystitis (n = 1) and appendicitis (n = 1); other disorders, including hemorrhoids (n = 8), hernia (n = 3), uterine prolapse (n = 1), intestinal obstruction (n = 2), gastric ulcer (n = 1), intestinal ulcer (n = 1), gallstone disease (n = 2), and malabsorption syndrome (n = 1). Post-operative cancer cases that were in complete remission (n = 4) were also included. We obtained written informed consent from all patients, and the study was approved by the institutional ethics committees at the Tokyo Metropolitan Institute of Medical Science and Tokyo Metropolitan Komagome Hospital. The clinical stage of the disease was determined according to the tumor-node-metastasis classification. Urine samples from 52 healthy volunteers (27 males and 25 females, ages 22-52 years) were also obtained. All the urine samples were collected in the morning, immediately supplemented with 3 mmol/L NaN3 and stored at –20°C until use. Under these conditions, polyamines are stable for at least 10 years, and analyses of the same sample on different occasions gave consistent results.
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Table 1. Summary of DiAcSpm levels in benign gastrointestinal disease cases and postoperative cancer cases in complete remission
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DiAcSpm in urine was measured by ELISA essentially as described previously (6). DiAcSpm-specific antibody was obtained from rabbit antiserum against N-acetylspermine coupled to mercaptosuccinylated bovine serum albumin via N-(4 -maleimidobutyryloxy)succinimide through several steps of affinity purification to minimize the cross-reaction with N1-acetylspermidine (N1-AcSpd), which would otherwise severely interfere with the determination of DiAcSpm (6). Cross-reaction of this purified DiAcSpm-specific antibody with N1-AcSpd was reduced to 0.03%, and the accuracy of the ELISA system using this antibody was verified by comparing the analytic results with those obtained with high-performance liquid chromatography (6) and mass spectroscopy measurements (7). We made the following slight modification of the ELISA system: AcSpm was conjugated to a peptide, WMQSWYYHWGGGTFPIC, via N-(8-maleimidocapryloxypropyl)succinimide to make a solid-phase antigen to obtain more stable attachment of the resulting AcSpm-conjugated (DiAcSpm mimicking) antigen peptide to the microtiter plate than that in the previous system. DiAcSpm was a kind gift from Drs. K. Samejima and A. Shirahata at the Josai University, Saitama, Japan. The creatinine concentration in the urine samples was determined enzymatically using Determiner L CRE (Kyowa Medex, Tokyo, Japan). Serum CEA, CA19-9, and CA15-3 values were determined at the Clinical Laboratory, Tokyo Metropolitan Komagome Hospital. The following values were used as cutoff values: DiAcSpm, 0.25 µmol/g creatinine (mean ± 2 SD for 52 healthy persons); CEA, 5 ng/mL; CA19-9, 37 units/mL; CA15-3, 23 units/mL. Using these cutoff values, 95% to 98% of healthy persons were negative with respect to a given marker.
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Results
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DiAcSpm was found a sensitive marker for colon and breast cancers. The urinary DiAcSpm level (in µmol/g creatinine) before surgical operation or chemotherapy in colon and breast cancer patients was compared with the levels in patients with nonmalignant diseases and in healthy persons, as shown in Fig. 1.
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Fig. 1. Sensitivity of DiAcSpm for colon cancer and breast cancer. Urinary DiAcSpm levels (percentiles) in cancer patients, patients with benign diseases, and healthy controls. DiAcSpm values are expressed as µmol/g creatinine and are in box plot format. Values included in each box, middle 50% of values of the studied population. Middle bar, median value, with the 95% confidence interval (notches). Values included between the bottom and top bars, values of 90% of the population. Dots outside the bars, values of the remaining individuals. Points above 4.0 µmol/g creatinine (8 and 1 among colon and breast cancer patients, respectively) are omitted. Raw median values (with ranges in parentheses) of DiAcSpm for 248 colon cancer patients, 83 breast cancer patients, and 52 healthy controls were 0.457 µmol/g creatinine (0.035-24.6), 0.283 µmol/g creatinine (0.069-6.4), and 0.139 µmol/g creatinine (0.077-0.285), respectively. Solid symbols in the benign disease group are patients who were in the active phase of inflammatory bowel diseases (see text).
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The sensitivity of DiAcSpm (100 x number of true positives / total patients) in the 248 colon cancer and 83 breast cancer patients examined was 75.8% and 60.2%, respectively, in reference to the cutoff value (mean ± 2 SD of healthy persons), whereas the specificity of DiAcSpm (100 x number of true negatives / total subjects in a control group) was 96% for the 52 apparently healthy controls and 77% for the 51 benign disease cases (Table 1). The raw median value for patients with benign diseases (with the range in parentheses) was 0.148 µmol/g creatinine (0.027-1.48). Patients with active inflammatory symptoms, including those with acute appendicitis (0.413 µmol/g creatinine) or acute cholecistitis (0.282 µmol/g creatinine) and those in the active phase of inflammatory bowel diseases tended to give DiAcSpm values above the cutoff level. Inflammatory bowel diseases were sometimes accompanied by unusually high levels of DiAcSpm (1.48, 1.19, and 0.74 in ulcerative colitis, Crohn's disease, and radiation enterocolitis, respectively). These cases are indicated by solid symbols in Fig. 1. Except for these cases with easily discernible active inflammation, patients with benign diseases had DiAcSpm values closely similar to those of healthy persons on average, with mean ± SD values of 0.16 ± 0.10 µmol/g creatinine compared with 0.15 ± 0.05 µmol/g creatinine for healthy persons, and their urinary DiAcSpm values did not usually exceed twice the cutoff values. It is worth noting here that only 2 of 15 adenoma cases were DiAcSpm-positive (0.34 and 0.41 µmol/g creatinine), and other cases of benign tumors, including two cases of carcinoid, one case of neurilemoma, and once case of lipoma, showed DiAcSpm values below the cutoff level. The specificity of DiAcSpm as a malignant tumor marker for these benign tumors (n = 19) was 90%.
Serum CEA and CA19-9 levels in colon cancer patients were measured and their sensitivity for the detection of colon cancer was compared with that of urinary DiAcSpm (Fig. 2). The sensitivity of DiAcSpm was much higher than that of these tumor markers currently in clinical use. The analytic data were normalized by the cutoff value of each marker and plotted as in Fig. 1. The sensitivity of DiAcSpm for colon cancer (75.8%) was significantly higher than the sensitivities of CEA (39.5%, P < 0.0001) and CA19-9 (14.1%, P < 0.0001). For these colon cancer cases, the raw median values (with ranges in parentheses) were 0.457 µmol/g creatinine (0.035-24.6) for DiAcSpm, 3.14 ng/mL (0-5.5 x 102) for CEA, and 10.9 units/mL (0-1.3 x 103) for CA19-9. The sensitivity was increased to 84.2% when a patient positive with respect to either DiAcSpm, CEA, or CA19-9 was defined as positive (P = 0.018 compared with DiAcSpm alone by 2 x 2 
2 test).
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Fig. 2. Sensitivity of DiAcSpm, CEA, and CA19-9 for colon cancer. Urinary DiAcSpm level (percentiles), serum CEA level (percentiles), and serum CA19-9 level (percentiles) in colon cancer patients are in box plot format as in Fig. 1. Shaded area, range below the cutoff values of the respective markers (0.25 µmol/g creatinine, 5 ng/mL, and 37 units/mL for DiAcSpm, CEA, and CA19-9, respectively).
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Serum CEA and CA15-3 levels in breast cancer patients were measured, and their sensitivity for the detection of breast cancer was compared with that of DiAcSpm in urine (Fig. 3). The analytic data were normalized by the cutoff value of each marker. The sensitivity of urinary DiAcSpm for breast cancer (60.2%) was also significantly higher than the sensitivities of serum CEA (37.3%, P = 0.0032) and CA15-3 (37.3%, P = 0.0032). For breast cancer cases, the raw median values (with ranges in parentheses) for DiAcSpm, CEA, and CA15-3 were 0.283 µmol/g creatinine (0.069-6.4), 3.6 ng/mL (0-4 x 105), and 14.2 units/mL (4.6-7.6 x 102), respectively.
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Fig. 3. Sensitivity of DiAcSpm, CEA, and CA15-3 for breast cancer. Urinary DiAcSpm level (percentiles), serum CEA level (percentiles), and serum CA15-3 level (percentiles) in breast cancer patients are in box plot format as in Fig. 1. Shaded area, range below the cutoff values of the respective markers (0.25 µmol/g creatinine, 5 ng/mL, and 23 units/mL for DiAcSpm, CEA, and CA15-3, respectively).
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One of the most potentially useful features of DiAcSpm is that it can detect early-stage colon and breast cancers in patients. The sensitivity of DiAcSpm and other markers was compared among colon cancer patients grouped according to tumor stage (Table 2). The proportion of positives with respect to each marker increased with the progression of the cancer, but the sensitivity of DiAcSpm was higher than the sensitivities of CEA and CA19-9 at every clinical stage. Notably, DiAcSpm values were above the cutoff level in 60% of stage 0 and I colon cancer patients, whereas only 10% and 5% of early-stage colon cancer patients were CEA- or CA19-9–positive, respectively. The difference in the sensitivity between DiAcSpm and CEA, and that between DiAcSpm and CA19-9, was significant for both stage 0 (P = 0.002 and 0.0004, respectively; n = 20) and stage I (P < 0.0001 and P < 0.0001, respectively; n = 40) patients. Combination of DiAcSpm with CEA and CA19-9 did not significantly improve the sensitivity of early-stage cancer detection compared with DiAcSpm alone. It is important that adenoma, carcinoid, and other benign tumor cases were mostly DiAcSpm negative, as described above. This indicates that urinary DiAcSpm may efficiently discriminate between benign and malignant tumors.
The proportion of positives with respect to each marker also increased with the progression of breast cancer, and the sensitivity of DiAcSpm was again higher than the sensitivities of CEA and CA15-3 at every clinical stage (
). The sensitivity of DiAcSpm for earlier stage breast cancer (stages I and II; 28.1%) was not as high as that for early-stage colon cancers but was significantly higher than those of CEA (3.1%, P = 0.018) and CA15-3 (0%, P = 0.0010). It should be noted that the sensitivity of these currently available markers for the detection of breast cancer at earlier stages was negligibly low.
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Discussion
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Serum CEA and CA19-9 have been widely used as tumor markers for colon cancers. The present study showed that the urinary DiAcSpm level is much more sensitive than these established tumor markers for detecting colon cancers. Patients with active inflammatory symptoms also tended to have high DiAcSpm values, but these patients could be easily identified by their characteristic symptoms. Besides these easily discernible patients, those who were being treated for benign diseases generally excreted similar amounts of DiAcSpm as healthy persons. Urinary DiAcSpm may thus be considered a novel high-performance tumor marker for colon cancers that can be favorably compared with the markers CEA and CA19-9. The urinary DiAcSpm level was also frequently elevated in breast cancer cases. Its sensitivity was significantly higher than that of established markers such as CEA and CA15-3. Our previous analysis using high-performance liquid chromatography procedure indicated that DiAcSpm was elevated frequently and markedly in urogenital malignancies, including prostate cancer, testicular cancer, renal cancer, and renal pelvic cancer, with a very low false-negative incidence (2). Further examination revealed that urinary diacetylpolyamines tended to decrease when cancer patients entered partial remission. The prognosis of patients was generally good when the diacetylpolyamine level was normal or nearly normal, whereas the prognosis was poor when the diacetylpolyamine level remained far above the normal limit after apparently effective treatment (3). DiAcSpm in urine was also reported to be increased in patients with leukemia (8, 9). The present results together with these previous observations strongly suggest that DiAcSpm may be useful to detect a wide variety of neoplastic diseases and that more extensive and detailed analyses of the usefulness of DiAcSpm as a diagnostic and prognostic marker for these as well as other types of cancer are warranted.
It is particularly important that DiAcSpm was frequently increased in urine from stages 0 and I colon cancer patients. Serum CEA and CA19-9 are virtually unable to detect these early-stage colon cancers. Moreover, DiAcSpm was not usually increased in cases of adenoma, thus allowing us to discriminate between malignant and nonmalignant tumors. The sensitivity of DiAcSpm for detecting early-stage colon cancer was comparable with that of the fecal occult blood test, which is widely used in screening for colon cancer. DiAcSpm was also able to detect the occurrence of early-stage breast cancer that could not be detected by either CEA or CA15-3. Early diagnosis is of great importance in cancer therapy, because cancers can often be cured if detected early enough, owing to the recent progress in cancer therapy. The availability of a tumor marker that would enable us to find cancers in patients at an earlier stage than is possible using currently available methods would contribute much to reducing fatal cases of cancer. DiAcSpm seems a promising candidate for such a marker. Urine samples are easily obtained noninvasively from individuals and are thus suitable test materials for analysis in health examinations. In addition, highly specific anti-DiAcSpm antibody was obtained and a simple procedure to determine urinary DiAcSpm was established and is available (6). For these reasons, we suggest that urinary DiAcSpm be used in health examinations as a sensitive marker for screening cancer patients at early stages.
Actively proliferating cells tend to excrete more polyamines as a result of the activation of intracellular polyamine metabolism and turnover. Vujcic et al. recently reported that MCF-7 breast cancer cells accumulate DiAcSpm together with N1-acetylspermidine and N1-acetylspermine on conditional overexpression of spermidine/spermine N1-acetyltransferase, and that this overexpression leads to growth inhibition of the cells (10). Chen et al. also observed an increase in DiAcSpm level associated with the induction of spermidine/spermine N1-acetyltransferase in melanoma cell lines treated with polyamine analogues (11). The induction of spermidine/spermine N1-acetyltransferase stimulates oxidative catabolism of polyamines on the one hand, and excretion of acetylated polyamines on the other, together leading to down-regulate the elevated cellular polyamine level and thus, suppress their uncontrolled growth (12). This may represent a homeostatic mechanism to lower intracellular polyamines under conditions of sustained high levels of ornithine decarboxylase in cancer cells. It is also possible that increased excretion of acetylpolyamines, including DiAcSpm, from cancer cells may be a consequence of a feedback response of rapidly growing cells in the tissues to down-regulate the elevated cellular polyamine level to suppress their uncontrolled growth.
Polyamines excreted into the circulation are once filtered through the glomerular basement membrane in the kidney, but a significant portion of them is soon reabsorbed from the glomerular filtrate into tubular cells and is reused in the body. Monoacetylpolyamines are recovered from the glomerular filtrate and converted by cellular polyamine oxidase to yield free polyamines to replenish the cellular polyamine pool (13). Measurement of polyamine uptake using polarized cultured cells derived from renal proximal tubular cells indicated that monoacetylpolyamines were actively transported into the cells from the apical surfaces, whereas DiAcSpm was not.7 It is likely that DiAcSpm excreted from cells is recovered in the urine without significant loss, whereas the amount of urinary monoacetylpolyamines is diminished by an indeterminable proportion compared that originally excreted from the cells in the body due to renal reabsorption and reutilization. This may provide a partial explanation of why the urinary level of DiAcSpm reflected the presence of cancer in the body with high sensitivity and at early clinical stages, whereas the urinary levels of monoacetylpolyamines failed to do so.
Mechanisms underlying the increased excretion of DiAcSpm in the urine of cancer patients as well as further clinical significance of urinary DiAcSpm measurement are currently under investigation in our laboratory.
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Footnotes
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Grant support: Ministry of Education, Culture, Sports, Science and Technology of Japan grants-in-aid for scientific research and Suzuken Memorial Foundation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: C. Tanaka is currently at the Department of Radiology, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.
7 T. Miki, et al., unpublished observation. 
Received 11/ 9/04;
revised 12/16/04;
accepted 1/ 6/05.
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- Vujcic S, Halmekyto M, Diegelman P, et al. Effects of conditional overexpression of spermidine/spermine N1-acetyltransferase on polyamine pool dynamics, cell growth, and sensitivity to polyamine analogs. J Biol Chem 2000;275:38319–28.[Abstract/Free Full Text]
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Abstract
Materials and Methods
