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Plasma Glutathione S-Transferase P1-1 as a Prognostic Factor in Patients with Advanced Non-Hodgkin’s Lymphoma (Stages III and IV)

¹ Fourth Department of Internal Medicine, Sapporo Medical University, School of Medicine, Sapporo, Japan; and ² Department of Clinical Pathology, Sapporo Medical University Hospital, Sapporo, Japan; and ³ Department of Oncology, Sapporo National Hospital, Sapporo, Japan

	ABSTRACT

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Purpose: This study aims to investigate whether the plasma level of glutathione S-transferase P1-1 (GSTP1-1), which is a phase II detoxifying enzyme known to be a resistance factor for anticancer drugs, could be a prognostic factor of de novo non-Hodgkin lymphoma (NHL) in clinical stages (CSs) III and IV.

Experimental Design: Study population consisted of 80 NHL patients with no prior treatment: 12 patients were at CS I, 14 at CS II, 25 at CS III, and 29 at CS IV. All 54 patients at CS III or CS IV were treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). Plasma GSTP1-1 concentration was measured by ELISA. We stained lymph node tissues for GSTP1-1 using anti-GSTP1-1 monoclonal antibody 5F and quantitatively assessed the intensity of immunostaining by using the KS-400 image analyzing system.

Results: There was a significant stepwise increment of plasma GSTP1-1 concentration from CS I to CS IV (P < 0.05). Of the 54 patients with CS III or IV treated with CHOP, 28 (52%) had elevated plasma GSTP1-1 levels. Plasma GSTP1-1 concentration tended to correlate with the intensity of GSTP1-1 expression in lymphoma tissues as assessed by immunostaining (P = 0.07). The CR rates in patients at CS III and CS IV treated by CHOP, 55.2% (14 of 26) and 16.0% (5 of 28) for the low and high plasma GSTP1-1 groups, respectively, were significantly different (P < 0.01). For these two groups, the median survival times were 64 and 25 months, respectively (P < 0.01), and the median times to progression were 58 and 12 months, respectively (P < 0.01). There was no significant correlation between plasma GSTP1-1 concentrations and other NHL prognostic indicators in these patients as determined by univariate and multivariate analyses.

Conclusion: These results showed that plasma GSTP1-1 is a useful prognostic factor for CS III and IV advanced NHL. Thus, it may be a promising strategy to treat NHL concomitantly with anticancer drugs and GSTP1-1-specific inhibitors.

	INTRODUCTION

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Although therapy for advanced non-Hodgkin’s lymphoma (NHL) has greatly improved over the last two decades, prognosis for approximately half of the patients remains poor. Factors defining prognosis in NHL are those related to tumor burden [clinical stage (CS), lactate dehydrogenase (LDH), extranodal involvement, etc.], status of patients (performance status, age, etc.), and tumor cell properties [histologic aggressiveness, expression of genes relevant to cell survival (p53, bcl-2), drug-resistant factors, etc; refs. 1, 2, 3, 4, 5 ]. As chemotherapy is inevitable for treatment of NHL at advanced stages such as III and IV, drug resistance factors may be one of the most viable prognosis defining factors. However, the implication of drug resistance factors for prognosis of NHL has not been carefully elucidated.

Drug resistance is generally mediated by metabolic pathways, including phase I and phase II enzymes and the phase III efflux pump system. Phase I enzymes such as cytochrome p450s exert their function through oxidation, reduction, and hydrolysis of xenobiotics. Of the cytochrome p450 isozymes, CYP1B1 is known to be expressed in tumor cells (6) , but it is reported to inactivate only one anticancer drug, docetaxel, nonrelevant to NHL treatment (7) . The phase III efflux pump, such as P-glycoprotein (multidrug-resistant factor), multidrug resistance-related protein and glutathione S-conjugate pump (GS-X), which actively pump out xenobiotics from the cells, have been shown to be involved in the inactivation of a wide variety of anticancer drugs, including adriamycin, vincristine, and VP-16 (8, 9, 10) . However, multidrug-resistant factor is reportedly irrelevant to the prognosis of NHL (11 , 12) , possibly because it is mainly implicated in acquired drug resistance (13 , 14) . Multidrug resistance-related protein is also reportedly proven not to be correlative to the prognosis of NHL (15) . Phase II enzymes such as aldehyde dehydrogenase-3, UDP-glucuronyltransferase, and glutathione S-transferase, which conjugate xenobiotics to inactivate them, are also known to be resistant factors to certain anticancer drugs. Aldehyde dehydrogenase-3 catalyzes the detoxification of cyclophosphamide, oxazaphosphorine, ifosfamide, etc. (16) , and UDP-glucuronyltransferase conjugates mitoxantrone but not adriamycin or vincristine, which are routinely used for treating NHL (17) . Glutathione S-transferase, on the other hand, has been shown to function as a multidrug-resistant factor for melphalan and chlorambucil by glutathione conjugation, and for adriamycin, cyclophosphamide and CDDP by a conjugation-unrelated mechanism (18, 19, 20, 21, 22, 23, 24) . This enzyme is often increased in malignant tissues, irrespective of prior chemotherapy, and is suggested to serve as a multidrug-resistant factor in both inherent and acquired fashions (19 , 25 , 26) . In fact, there are recent reports that disclosed a correlation between glutathione S-transferase P1-1 (GSTP1-1) expression in tumor tissues and the prognosis in ovarian cancer as well as in head and neck cancer (27 , 28) .

There have been a few reports about GSP1-1 expression with special reference to their chemotherapy responsiveness in NHL. Berhame et al. (29) , applying immunohistochemistry, found no significant correlation between chemosensitivity and GSTP1-1 expression, but they dealt with only nine cases. Rodrigeuz et al. (30) obtained similar results using dot blot analysis, but 16 of the 41 cases they studied had anamnesis of prior chemotherapy and therefore are not suitable for analysis of prognostic factors. Ribrag et al. (31) studied GSTP1-1 expression by immunohistochemistry in 69 diffuse large B-cell lymphoma patients and found a significant correlation between the staining intensity and complete remission rate but not between the intensity and overall survival. They included 41 cases at stages I and II, which may not be suitable for studying prognostic factors because curability and prognosis of patients at these early stages may not merely reflect sensitivity of tumor cells to chemotherapy.

We have previously established an ELISA for plasma GSTP1-1 (32 , 33) . In the present study, therefore, we investigated whether or not the plasma GSTP1-1, which reflects the sum of GSTP1-1 expression in total multiple lesions, could be a predictor of the response to cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP) treatment and/or the prognosis of untreated NHL (stage III or IV).

	MATERIALS AND METHODS

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Subjects.
This study was approved by the ethics committee of Sapporo Medical University. Eighty patients who were histopathologically diagnosed as having NHL at the 4th Department of Internal Medicine of Sapporo Medical University Hospital and affiliated hospitals during the period of January 1994 to March 1999 were enrolled after strict informed consent was provided by each patient. The study group consisted of 43 males and 37 females, with a mean age of 60 years (27–79). All lymphoma tissues were histologically evaluated by two independent reviewers (M. S. and T. I.) in the Department of Clinical Pathology of Sapporo Medical University. Forty-two patients were diagnosed as having diffuse large B-cell lymphoma, 30 with low-grade B-cell lymphoma, 3 with marginal-zone B-cell lymphoma, and 2 with lymphoblastic lymphoma in accordance with the World Health Organization classification (34) . Lymphomas were also classified as indolent type (30 low-grade B-cell lymphomas and 3 marginal-zone B-cell lymphomas), aggressive type (42 diffuse large B-cell lymphomas) or very aggressive type (2 lymphoblastic lymphomas) according to the criteria of the International Lymphoma Study Group (35) . The distribution of clinical stages was 12 patients in CS I, 14 in CS II, 25 in CS III, and 29 in CS IV.

Blood samples were kindly provided by forty healthy volunteers with strict informed consent.

Chemotherapy Protocol.
All of the patients at CS III or CS IV were treated with CHOP (750 mg of cyclophosphamide per square meter of body-surface area, 50 mg adriamycin per square meter, and 1.4 mg of vincristine per square meter (up to a maximal dose of 2 mg) on day 1 as well as 40 mg of prednisolone per square meter per day for 5 days; ref. 36 ) and were treated every 3 weeks for 8 cycles. Treatment was stopped if lymphoma progressed, if the patients declined to continue or at the discretion of the investigator in cases of either intercurrent illness, or where adverse effects were displayed.

Tumor responses were assessed after 8 cycles of chemotherapy or at the end of treatment and were judged as complete response, unconfirmed complete response, partial response, stable disease, or progressive disease according to the response criteria of the International Workshop (37) .

Plasma GSTP1-1 Measurement by ELISA.
Before treatment, blood samples were gently drawn from the cubital vein of the patients by syringes that had been wetted with EDTA-2Na and transferred to plastic tubes containing EDTA2Na. They were then immediately centrifuged at 1,200 x g at 4°C for 15 minutes. Plasma samples were separated with a Pasteur pipette, taking care to avoid collecting platelets or blood cells, and filtered through millipore membrane (0.45 µm) to avoid contamination of blasts. Samples were stored at –20°C, and after thawing to room temperature, we subjected them to a sandwich ELISA using monoclonal and polyclonal antibodies established in our laboratory (32 , 33) .

Immunohistochemical Analysis of GSTP1-1.
Lymph node tissues biopsied from patients before treatment were fixed in formalin and embedded in paraffin. Then we cut the tissues into sections 3-µm thick and stained for GSTP1-1 using the mouse monoclonal antibody 5F (32) or for controls using normal mouse IgG (DAKO, Glostrup, Denmark) for the first antibodies and biotinylated horse antimouse immunoglobulin G (Vector Laboratories, Burlingame, CA) for the second. GSTP1-1 protein was visualized with a Vectastain ABC kit (Vector Laboratories) using 3–3'-diaminobenzidine (Sigma Chemical Co. St. Louis, MO) as a chromogen. Hematoxylin was not used because it would have disturbed the assessment of immunostaining intensity by the imaging analyzer. We also did the immunostaining for CD20 in the serial sections to examine the percentage of lymphoblasts. We carried our image analysis of staining for GSTP1-1 by using an AxioCam photomicroscope and the KS-400 image analyzing system (Carl Zeiss Vision GmbH, Hallbermoss, Germany) in accordance with the method of Kato et al. (38) with minor modifications. In brief, five randomly selected microscopic images 50 x 50 µm² each, in which the percentages of lymphoblasts were more than 90%, were selected. They were imported into the KS400; brown-stained areas, which represented positively stained GSTP1-1 in each lymphoma cell, were converted into a 255-grade gray scale. The sum of gray scale intensities in each 50 x 50 µm² square was calculated by using the KS-400 image analyzing program, and the relative intensity was represented by the ratio of the intensity to that of the serial section immunostained by normal mouse IgG. The mean of the five relative intensities in each section was calculated.

Statistical Analysis.
Correlations between the plasma GSTP1-1 concentration and the clinical stage or the histologic classification were assessed by the Kruskal-Wallis test. The correlation between plasma GSTP1-1 concentration and intensity of GSTP1-1 expression was assessed by the Pearson’s test. The correlation between the CR rates and relative intensity of GSTP1-1 expression was assessed by the ² test. The correlations between the CR rates and plasma GSTP1-1 concentration or factors from the International Prognostic Index (1) were assessed by Fisher’s exact probability test. Correlations between the plasma GSTP1-1 concentration and progression-free or overall survival curves were constructed with the Kaplan-Meier method. Multivariate analysis was done with the COX proportional hazards model.

	RESULTS

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Plasma GSTP1-1 Concentration in NHL.
The mean plasma GSTP1-1 concentration in 40 healthy subjects was 13.8 ± 4.4 ng/mL. The cutoff value was set at 22.6 ng/mL, which was the mean + 2SD (Fig. 1A) . There was a significant stepwise increment of plasma GSTP1-1 concentration from CS I to CS IV (Kruskal-Wallis test, P < 0.05), although no significant difference was observed between those of CS III and CS IV. Of the 54 patients with CS III or IV, 28 (52%) had elevated plasma GSTP1-1 levels. There was no statistical difference between any indolent, aggressive, or very aggressive lymphoma (P = 0.64, Fig. 1B ). Because CS I or CS II NHL is not usually treated with chemotherapy and therefore not relevant for GSTP1-1 study, further investigation was done only on CS III and CS IV NHL.

View larger version (24K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Plasma GSTP1-1 concentrations in patients with NHL of various clinical stages (A) and histologic types (B). The cutoff value was set at 22.6 ng/mL (mean + 2SD). There was a significant stepwise increment from CS I to CS IV (Kruskal-Wallis test, P < 0.05). There was no significant difference among the histologic types.

View larger version (114K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Immunohistochemical staining for GSTP1-1 in lymphoma tissues. A, H&E of lymphoma tissue. B, representative lymphoma tissue strongly stained for GSTP1-1. C, 50 x 50 µm2 field from the panel B. D, H&E of lymphoma tissue. E, representative lymphoma tissue weekly stained for GSTP1-1. F, 50 x 50 µm2 field from the panel E. G, H&E of lymphoma tissue. H, representative lymphoma tissue negative for GSTP1-1. I, 50 x 50 µm2 field from panel G.

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. Relationship between plasma GSTP1-1 concentration and immunohistochemical GSTP1-1 expression level in biopsied lymphoma tissues. The plasma GSTP1-1 concentration tended to correlate with relative intensity of immunohistochemical staining; the correlation was not statistically significant (r = 0.45, P = 0.07).

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Fig. 4. Kaplan-Meier analysis of overall survival in high and low intensity groups of GSTP1-1 expression in NHL. Relative intensity of immunohistochemical staining in biopsied lymphoma tissue of each case was calculated as described in "Materials and Methods." There was no significant difference in overall survival between high and low intensity groups (P = 0.31).

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Fig. 5. Kaplan-Meier analysis of overall survival in high and low plasma GSTP1-1 groups of NHL. There was a significant difference in overall survival between the two groups (P < 0.01).

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Fig. 6. Kaplan-Meier analysis of progression-free survival in high and low plasma GSTP1-1 groups of NHL. There was a significant difference in progression-free survival between the two groups (P < 0.01).

	DISCUSSION

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GSTP1-1 is known to conjugate melphalan and chlorambucil with glutathione and export them through the GSX pump. GSTP1-1 has also been shown to endow resistance to 4-HC, the active form of cyclophosphamide, and adriamycin through a conjugation-unrelated mechanism (18 , 19 , 39) . Although the mechanism of the conjugation-unrelated resistance has not yet been elucidated in detail, it has been proposed recently that GSTP1-1 endows resistance to apoptosis through inhibition of JUN kinase pathway (18) . It is also another plausible mechanism that GSTP1-1 sequestrates these drugs in cytosol by direct binding (40) .

Furthermore, we evidenced an independency of plasma GSTP1-1 from other previously accepted prognostic factors, which include age, serum LDH, performance status, clinical stage, and extranodal involvement; this may be reasonably accepted because none of these factors are related to drug resistance whereasGSTP1-1 is.

An obvious advantage of using GSTP1-1 in circulation rather than in tissue as a prognostic marker is, needless to say, the objectiveness in quantitative analysis. Even more importantly, GSTP1-1 expression in a biopsied lymphoma tissue does not necessarily represent that in multiple lesions because malignant tissues are generally heterogeneous (41 , 42) , whereas plasma GSTP1-1 level is believed to reflect the sum of GSTP1-1 expression in each lymphoma tissue. Should an advanced patient whose biopsy specimen is negative for GSTP1-1 undergo CHOP therapy, the prognosis may be poor because other lymphoma tissues express high levels of GSTP1-1 and are resistant to CHOP. In fact, in the present study, expression of GSTP1-1 in lymphoma tissue, which did not correlate with plasma GSTP1-1 levels, was not a good indicator of chemotherapy responsiveness or prognosis, in agreement with previous reports (29, 30, 31) .

The postulation that plasma GSTP1-1 reflects the sum of GSTP1-1 expression may be supported by the fact that GSTP1-1 concentrations in culture media of various tumor cell lines well correlate with those of their respective cell lysates (data not shown). With regard to the mechanism of GSTP1-1 being released from cells, it may not be simple leakage because GSTP1-1 in the medium exists in monomer form unlike the intracellular form, which is a homodimer (43) .

Analyses of the gene expression profile of diffuse large B-cell lymphoma by using DNA microarray have been reported recently by three independent groups (44, 45, 46) . Arizadeh et al. (44) and Rosenwald et al. (45) used a common customized cDNA microarray "lymphochip" that did not include the cDNA of the GSTP1-1 gene. Shipp et al. (46) used a customized oligonucleotide microarray "HU6800," which could detect GSTP1-1 gene expression, although their gene expression profile, which determined the prognosis of NHL, did not include that of the GSTP1-1 gene. However, the stage distribution of their cases was uncertain. More importantly, their investigation was carried out with a biopsied specimen, which does not necessarily represent scattered multiple lesions of NHL at advanced stages. It has been also suggested that the microarray analysis they used was less sensitive than conventional methods such as real-time PCR and Northern blotting. For example, Rajeevan et al. (47) reported that differences <4-fold detected by the microarray method were not always reproducible by real-time PCR.

Incidentally, a report by Schisselbauer et al. (48) indicated that glutathione S-transferase in blasts of chronic lymphatic leukemia was relevant to chlorambucil resistance. This apparently contradicts our present claim that the concentration of glutathione S-transferase in tumor cells may not represent that of total tumor mass in the body because of tumor heterogeneity. However, in chronic lymphatic leukemia, needless to say, blasts are circulating and, unlike lymphoma, heterogeneous sampling could be avoided. Therefore, their results were compatible with ours analyzed by plasma GSTP1-1 measurement in NHL.

Nonetheless, the plasma GSTP1-1 concentration is thus considered to be a useful prognostic factor for NHL at advanced stages.

	ACKNOWLEDGMENTS

 
We thank Dr. Ohtani for valuable advice on immunohistochemical staining. Thanks to K. Litton, bachelor of English literature, for correction of the English in this manuscript.

	FOOTNOTES

 
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.

Requests for reprints: Yoshiro Niitsu, Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan. Phone: 81-11-611-2111, ext. 3260; Fax: 81-11-612-7987; E-mail: niitsu{at}sapmed.ac.jp

Received 12/ 4/03; revised 8/15/04; accepted 8/31/04.

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