Glucocorticoid Receptors and Steroid Sensitivity in Normal and Neoplastia Human Lymphoid Tissues: a Review1

[CANCER RESEARCH 44, 431-437, February 1984]

Glucocorticoid Receptors and Steroid Sensitivity in Normal and Neoplastia Human Lymphoid Tissues: A Review1

FranÃ§oiseHomo-Delarche

INSERM U7, Physiology and Pharmacology, HÃ´pital Necker, 161 rue de SÃ¨vres, 75015 Paris, France

This paper presents a critical review of GR2 determination as Abstract an index of steroid sensitivity in normal and leukemic human The determination of estrogen and progesterone receptors in lymphoid tissue. breast cancer has been shown to be useful in predicting the response to endocrine therapy. Given their well-known inhibitory Normal human lymphoid cells effects on lymphoid tissue, glucocorticoids have been used widely in the treatment of leukemia. Given these facts, over the Although many studies have attempted to determine the ef last 10 years, several investigators have measured the number fects of glucocorticoids on leukemic lymphoid tissues, only a few of glucocorticoid receptors in normal and neoplastic lymphoid have actually related the extent of steroid action in normal human tissue to see whether their number correlated with glucocorticoid lymphoid cells to the level of GR. responsiveness in vitro or in vivo. No clear correlation could be As shown in Table 2, the number of GR was determined by whole-cell assay in children's thymocytes and bone marrow as established between the level of glucocorticoid receptor and the in vitro action of steroids in normal and neoplastic lymphoid well as in adult blood and lymph node lymphocytes in a number tissue. In contrast, attempts to correlate glucocorticoid receptor of studies (5,13,31,32,36,43,46, 56,58,63,70). It is apparent levels in acute lymphocytic leukemia to in vivo steroid respon that the number of binding sites found in blood lymphocytes is siveness and immunological type using the whole-cell-binding very similar in the various reports and ranged from 3 to 7000 sites per cell with a Â«<,ofaround 10~8 M. No significant difference assay for receptor determination and selecting the patients ac cording to age and immunological criteria have been more suc could be seen between normal T- and B-cells, but it has been cessful. suggested that T-cells are heterogeneous with respect to their quantity of GR (17). On the other hand, the number of receptors measured in either human thymus cells or lymph node lympho Introduction cytes was comparable to that of blood lymphocytes. In contrast, It has been known for a long time that glucocorticoids exert GR levels in normal bone marrow were 3 to 5 times higher than in other lymphoid tissues (13). Monocyte depletion prior to the many physiological and pharmacological effects on mammalian lymphoid tissues. In vivo administration of corticosteroids or determination of blood lymphocyte receptors appeared to be adrenalectomy has been shown to induce marked changes in necessary, since monocytes contain approximately 2 times more the size of lymphoid organs as well as in lymphocyte circulation receptors than lymphocytes (17, 46). and to alter many immunological reactions (11). In vitro, gluco If we consider the effect of steroids on cell viability, it appears corticoids are generally considered as catabolic agents that that human lymphoid cells are extremely resistant to them when compared to rodent lymphoid cells. Mouse thymocytes undergo induce an inhibition of membrane transport and macromolecular a 50% cell lysis after 6 hr incubation in the presence of 10"6 M synthesis leading to an arrest of cell growth, sometimes accom panied by cell lysis (54). These compounds are also able to dexamethasone (12, 34), whereas human lymphocytes are not modify several immunological functions in vitro (1). killed even during longer incubation (Table 3) (5, 26, 65). In These widespread effects on lymphoid cell metabolism and contrast, when another method to determine steroid action in function constitute the basis for the use of glucocorticoid hor vitro, i.e., its effect on nucleoside incorporation into RNA and mones in the treatment of a wide variety of immunological and DNA, is used, it is apparent that the glucocorticoid effect can be inflammatory diseases as well as in the treatment of lymphoid very different from one cell population to another (Table 3). cell neoplasias. Human thymocytes appeared to be extremely sensitive to the According to the classical mechanism of steroid hormone inhibitory action of steroids (32), whereas peripheral and lymph action, which includes a preliminary step of interaction of the node lymphocytes were less affected (5, 36). These differences steroid with cytoplasmic receptors (53), numerous studies have observed between thymocytes and peripheral lymphocytes are been devoted to the question of whether or not the receptor probably related to the stage of cell proliferation. Claman (11) content of lymphoid cells may be representative of the in vitro or postulated that the in vivo shrinkage of the infant thymus after in vivo sensitivity. The different methods used to measure steroid hydrocortisone administration could be explained in terms of receptor levels as well as in vitro and in vivo sensitivity are listed growth inhibition. Since the rate of cell division in infants is very in Table 1. high, any agent which blocks cell proliferation without changing intrathymic cell death would cause a decrease in thymus size (10-12). 1Part of this work was supported by Grant 76-7-1669 from DGRST, by Grant 58-78-90 from INSERM, and by the National Cancer Institute-INSERM Collaborative 2The abbreviations used are: GR, glucocorticoid receptor; ALL, acute lympho Agreement on Hormonal Regulation and Cancer (1976/1977). cytic leukemia; CLL, chronic lymphocytic leukemia; PBL, peripheral blood lympho Received May 5,1983; accepted October 6.1983. cyte.

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Table 1 receptors for the steroid were comparable to those determined Different experimental procedures for the determination of glucocorticoid in normal humans. It was recently demonstrated that the use of sensitivity a cytosolic assay instead of the whole-cell assay leads to a Receptor content Cytosol assay Whole-cell assay marked underestimation of the number of binding sites (up to Total binding (cytoplasmic + nuclear) 80%) (38, 49). Several reasons may account for this difference, Nuclear binding mainly the failure to measure the receptor in the nuclear com In vitro sensitivity Steroid effect on glucose and amino acid transport Steroid effect on precursor incorporation into proteins, partment, but also the release of proteolytic enzymes that par RNA, and DMA tially inactivate the receptor during cytosol preparation or even In vivo sensitivity Short-term response to glucocorticoids alone (variation in the failure to break some cells during homogenization. blast cell count) Response to combined chemotherapy It is now widely recognized that ALL is a strongly heteroge Achievement of complete remission neous disease with regard to its clinical and immunological Duration of complete remission Survival aspects. Several groups have thus attempted to establish a relationship between the number of receptors and the immuno logical markers. It appears that in the childhood form, "null" cell

With regard to the in vivo action of glucocorticoids in normal leukemia tends to contain more receptors than T-cell leukemia (15, 42, 57).3 The correlation with the immunological type ap humans, it has been shown that steroids induce in vivo a transient lymphopenia (20). Although both T- and B-lymphocytes peared less striking in adults (7, 36). Few data are available are removed from the circulation and sequestered in the bone concerning B-cell lineage, but pre-B-cells have been shown to possess as many receptors as "null" cells (15, 57).3 In a recent marrow, there is a proportionally greater depletion of circulatory T-lymphocytes, more precisely of a functionally defined T-cell study, GR levels were measured in bone marrow aspirates of subpopulation (19, 21). However, this selective lymphodepletive 174 children with newly diagnosed ALL (13). Bone marrow effect of glucocorticoids could not be explained on the basis of samples were selected with more than 90% of blast cells be detectable differences in GR levels in the different T-cell subpop- cause, as mentioned above, normal bone marrow exhibits a high ulations(21). level of GR. The number of binding sites ranged from 2,248 to 79,664 per cell (median, 18,123) and was higher than that reported previously in blood samples. The authors suggested Neoplastia human lymphoid tissue that this discrepancy may result either from cell storage (GR are Glucocorticoids have been used for more than 20 years in the relatively labile) or from a true difference between blood and treatment of leukemia, first alone and now as a part of combined bone marrow receptor content. Extensive comparative studies chemotherapy (4). It appears, however, that some patients either of GR levels in blood and bone marrow samples need to be are resistant to them at the outset or cease to be responsive performed, to give a definite answer (8, 13). As in blood, GR during the course of the treatment. Since determination of estro content is lower in the bone marrow of T-cell leukemia than in gen and progesterone receptors in breast cancer represents an that of common leukemia (13). In studies with a limited number important element in the therapeutic management of the disease of patients, no significant correlation has been found between (52), similar studies were carried out in cases of leukemia, in GR content of circulating cells and WBC or sex (33, 37, 42, 49). order to select in advance the patients who are likely to respond However, after studying a large number of cases, Costlow ef al. to steroid therapy. related low GR levels in bone marrow to ages <2 or >10 years, black race, high leukocyte count, central nervous system dis Acute Lymphocytic Leukemia ease, and mediastinal mass; all these parameters are recognized as high-risk features in the diagnosis of leukemia (13). Ten years ago, Lippman ef al. (47) first presented promising Attempts to correlate the level of GR in ALL with most of the results. They showed, using a cytosolic assay, that the cells of parameters of the in vitro sensitivity were unsuccessful in most patients with previously untreated ALL contained high levels of of the studies (14, 30, 33, 37, 50). It may be possible to explain receptors. These cells were also sensitive to steroid action in the absence of correlation between the number of receptors and vitro as well as in vivo. They showed also that patients previously the in vitro effects of steroids by the heterogeneity of the cells. treated with corticosteroids who failed to respond to additional For this reason, we separated our patients into 2 groups on the treatment had barely detectable levels of receptors. In addition, basis of the absence or presence of blood cells in the S phase the cells of these patients were insensitive to steroids in vitro. of the cell cycle, using pulse cytophotometry analysis (33). It The potential clinical implication of this correlation between re appeared that the in vitro inhibitory effect of dexamethasone ceptor content and the in vitro or in vivo response to chemo was 2 times higher in the group of patients with cells in S phase therapy has prompted several groups to undertake comparable than in the group of patients without detectable cells in S phase. studies. The cytotoxic effect of cortisol was recently studied in different It soon appeared that, when assayed by the whole-cell types of ALL defined by monoclonal antibodies and rosettes method, all peripheral leukocytes isolated from patients with ALL (25). Lymphoid cells from 20 patients with common ALL were contain specific receptors for glucocorticoids (Table 4). The found to be resistant to cortisol, whereas the cells from 10 number of binding sites ranged from 1,000 to more than 20,000 patients with pre-B-leukemia were readily lysed. Cells from 5 (8, 15, 30, 33, 37, 42, 49, 56, 57).3 The affinities of these patients with "early" T-cell leukemia were sensitive, whereas cells from 2 patients with a more mature T-cell phenotype were

3F. F. Quddus, S. H. Kauffmann, M. Roper, B. Dowell, J. Pullen, and B. G. found to be resistant. This suggests that the in vitro effect of Leventhal. Glucocorticoid receptor (GR) level in pediatrie leukemia cells, personal glucocorticoids in terms of cell lysis may be linked to cell differ communication. entiation.

432 CANCER RESEARCH VOL. 44

Tabte2 Number of GR in normalhuman lymphoid cells (whole-cell assay) ofCell No. typeChildren's Refs.5(M) patients marrowChildren'sbone thymocytesAdult x10-'5.5 lymphocytesPBL(peripheral x10-"4 Non-T-cellt Â±1,068*3,130Â± x10-'3.5 xIO'87.1 T-cellPBLJ 1,3163,151 Â±7264,6803,6503,8754,850 x10-"5.6 x10~e5.1 T +null| B-cellPBLPBLPBLPBLAdult xIO"'4.8

+1,3407,069 Â±6826,617 10-"9910457551814189111332584646703636433156635GlucocorticoidÂ±9792,082aTable x nodes* lymph Median.6 Mean Â±S.D.GR13,929a3,1002,700a2,892

3K,, vitroThymocytesPeripheral sensitivity of normal human lymphoid cells in of[3Hluridineof Inhibition [^Ithymidineincorporation incorporation(%) conditionsCortisol Refs.>90 conditionsDexamethasone, (%)70.1 mg/ml,20Buccinate,1 26*60 M,24 10"6 3.920.4Â± 8.1s 95.9 Â± hrCortisol hrDexamethasone, M,24 10~Â° lymphocytesLymph Â»ig/ml,4succinate, 10 65Â»80 Â±19.328Â±12.9 23.8 daysDexamethasone, hrDexamethasone, M,4 4 x 10~7 M,20 10~7 node lymphocytesExperimental 5Experimental 21Refs.32365 daysCellviability(%) hrInhibition a Mean Â±S.D.

Table 4 Number oÃGRin ALL (whole-cell assay) of PatientsBlood ofleukemiaNullTNull KÂ«(M)patients3.9x10-'

27 ChildrenChildren 0-5,8872,560-19,160688-20,79119,7683.9x10-*183.9 x 10-"235 +adultsChildrenChildrenChildren+ B +TNull x 10-" 1912

T 4,077 1 BNull 2,85013,579 229

+adultsChildrenAdultsChildren Â±11,434a T +BPre-B 2,517.3214,171.6 Â± 810

,000 NullTNull 14,000 14 2,5001,348-18,6971 9147.7-46.1

+TCommon x 10-"1910-9 +adultsChildren 1Null + B + ,433-26,8588,495

adultsChildrenBone+ + B +TCommon ,6219,100Â±1 887

Â±7,500 Pre-B 8,000 Â±5,400 33 TCommon 4,200Â±3,1002,480-79,364(21,329Â°) 20122

marrow ChildrenType T 9,016-37,072 (9,016C) 35 1,115-8,872 (5,897e) B 5 9,265-29,574 (20,992e)No. UndifferentiatedSites/cell2,936-21,869 11Refs.42333757491583056613 3 Mean Â±S.D. 0 See Footnote 3. 0 Numbers in parentheses,median.

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Antileukemic therapy usually includes, in addition to glucocor- of the illness (35). Similarly, it was shown that CLL lymphocytes, ticoids, 2 or 3 other cytotoxic agents, and it is therefore difficult in contrast to normal PBL, were in vitro very sensitive to the to ascertain the clinical efficiency of one of these drugs and to cytotoxic action of glucocorticoids (26, 66). relate an in vivo response to the level of GR. To overcome this difficulty, several groups have attempted to correlate the level of Hairy Cell Leukemia receptors with the short-term response to glucocorticoid therapy. GR were measured by whole-cell assay in leukemic cells from By selecting the responsive patients on the basis of at least a 5 patients with hairy cell leukemia (44). GR sites ranged from 50% decrease in the number of circulating blast cells, the number 5,710 to 11,400 sites per cell, with a Â«<,of about 10~8 M. of receptors appeared to be slightly higher in the sensitive Glucocorticoid sensitivity studied in a cell line derived from one patients (8, 30, 33, 37, 49). of the patients showed, in fact, a stimulation of DMA synthesis. On the other hand, Lippman ef al. (48) were the first to compare in children the levels of receptors at diagnosis before any treat Non-Hodgkin 's Malignant Lymphoma ment with long-term combined chemotherapy. They showed that patients with high receptor levels tend to have "null" cell ALL Investigations of malignant lymph nodes were carried out in and a long remission duration. Patients with low receptor levels cell suspensions containing at least 50% malignant cells (5-7). have T-lymphoblasts and a short remission duration. Patients The number of binding sites measured by whole-cell assay varied with intermediate receptor levels had an intermediate and iden greatly from one patient to another but was on an average higher tical remission duration, regardless of the cell type. They con in cells from patients with non-Hodgkin's malignant lymphoma cluded that GR levels appear to have clinical significance inde than in cells isolated from control lymph nodes [median values pendently of age, WBC, or cell type and may represent a are 4110 (n = 42) and 2082 (n = 11) sites per cell, respec biological marker associated with other factors, which are related tively]. In addition, "null" cell lymphomas, as in ALL patients, to chemotherapy response, such as rate of growth or biochem usually contained more receptors than did T-cell lymphomas. ical differentiation. More recent studies in children confirmed that Finally, sequential investigations (at diagnosis and at relapse) low GR levels are associated with earlier and more frequent showed a decrease of the number of GR after treatment. relapse (13, 31, 49). In contrast, GR levels did not correlate with Despite the high sensitivity of lymphoma cells to the cytotoxic response to combined chemotherapy, duration of remission, or action of glucocorticoids in vitro (almost 50% of cell lysis after survival in adults (8). 96 hr incubation in the presence of 4 x 10~7 M dexamethasone), no correlation could be found between the level of these GR and Chronic Lymphocytic Leukemia any parameters of in vitro sensitivity. Determinations of GR have now been performed by several On the other hand, Bloomfield ef al. (5) have studied in 20 groups in more than 100 patients with CLL (24, 31, 35, 43, 56, patients the response to therapy with corticosteroids as a single 67, 69, 71, 72, 74). In the early studies performed by cytosolic agent. They showed in the group of responders (with a 50% or assay, the receptors were detected in only one-half to one-third more decrease in measurable tumor after corticotherapy) that of the patients. Again, when assayed by whole-cell assay, the the number of GR was significantly higher than in nonresponders presence of glucocorticoid-binding sites was detected in all (5600 versus 3300 sites, p < 0.01, n = 10, in each group). cases. The number of these receptors was on an average similar to or even slightly lower than that measured in normal PBL (Table Thymoma 5). More recently, Ho et al. (31) have demonstrated that the cells Ranelletti et al. (37, 60, 61) have studied the level of GR in from patients who were treated for 3 to 5 years with a combi various forms of thymus dysplasia. Using a cytosolic assay, they nation of corticoids and chlorambucil and became resistant to showed that the level of specific receptors was significantly this treatment contain lower receptor content than did cells from higher in lymphoepithelial thymoma than in pure epithelial form, newly diagnosed patients. in thymus hyperplasia, or even in normal thymus. However, Attempts made to correlate the amount of receptors with in despite this high level of GR, the in vitro sensitivity of thymoma vitro steroid sensitivity were unsuccessful (14, 31, 35, 71). It cells to glucosteroids was comparable to that of normal thymus appears, however, that the extent of dexamethasone-induced cells either in terms of inhibition of precursor incorporation or in inhibition of uridine incorporation was generally more important terms of steroid-induced cell lysis. in cells from CLL patients than in normal PBL and that this in vitro steroid sensitivity increased significantly with the severity SÃ©zarySyndrome

Table 5 Schmidt and Thompson (64) have studied the binding of Number of GR in CLL (whole-cell assay) tritiated dexamethasone in the circulating lymphocytes of 7 of patients with SÃ©zarysyndrome. Using a cytosolic assay, they patients211761161412Rets.35694331567214showed the presence of detectable specific receptors in 5 cases. TotalbindingNuclear Â±666a3850 Although one patient with very high levels of receptors was Â±7734500291 shown to be dramatically improved by prednisone treatment, whereas one patient with no detectable receptors was refractory 2Â±8842032 to combined chemotherapy, it also appears that 2 patients with bindingSites/cell4000-60003423Â±692119No. nonnegligible levels of receptors were not sensitive to combined chemotherapy including glucocorticoids. These authors also pro 1Mean Â±S.D. posed that the determination of the activity of the steroid-

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Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1984 American Association for Cancer Research. GR and Sensitivity in Human Lymphoid Tissues inducible enzyme glutamine synthetase might represent a useful ously believed. Gillis e? al. (27) demonstrated that inhibition of test for functional glucocorticoid action. mitogen-induced cell proliferation by steroids represents an in direct action (suppressing the production of a T-cell growth factor Discussion by a small subset of cells) rather than a direct action at the level of activated lymphocyte. Moreover, the in vitro sensitivity of After 10 years of research in GR and leukemia, it appears that leukemic blasts may not always reflect the in vivo response to the discrepancies seen among the results of the various studies combined chemotherapy. We have already seen that the re may be in part accounted for by differences in the selection of sponse to treatment as well as the number of GR appears more the patients and the experimental procedures used to determine probably dependent on the immunological type of the cells. receptor levels. It was recently demonstrated that high levels of GR were usually associated with the presence of terminal deoxynucleoti- Selection of the Patients and Target Tissue dyl transferase activity in lymphoid as well as in myeloid leukemic cells (55, 68). Although these results should be confirmed in For experimental convenience, most of the studies have been more extensive studies, including careful choice of patients and performed using peripheral leukocytes, although it is now well investigation of immunological markers, they suggest a relation recognized that blood cells do not entirely reflect the proliferative ship between the level of receptors and cell differentiation. activity of the bone marrow (51). Indeed, comparative studies Evaluation of the in vivo response to corticoid therapy is even performed in the same patients may show differences in GR more complex because it represents a combination of different levels between blood and bone marrow samples (8, 13). Bone mechanisms including, among others, inhibition of cell prolifera marrow, which is usually the main focus of tumoral proliferation, tion and cell lysis, but also cell recirculation and sequestration. may thus represent a more appropriate tissue for the study of In addition, it is obvious that in vivo the perturbations caused by glucocorticoid action, particularly in leukopenic patients. When steroid treatment on the general hormonal balance, on vascular the patients have been selected on the basis of more than 80 to function, and on immunological reactions may influence consid 90% of circulating or bone marrow blast cells, attempts to erably the evolution of leukemia (4). Nevertheless, there are now correlate GR levels with some other parameters (immunological some indications suggesting that the cells of ALL sensitive to type, response to combined chemotherapy) have been more successful. steroid therapy and/or chemotherapy tend to contain more re ceptor than do cells of nonresponders or patients who will Problems of Receptor Determination relapse. Finally, there are several aspects of steroid action which have Besides the technical problems of receptor determination, not been fully explored but may play an important role in neo- which have already been underlined (storage of the cells, cytosol plastic lymphoid tissues. Recent findings have shown the exist versus whole-cell assay), it should be kept in mind that receptor ence of a high level of transcortin in patients with lymphatic concentration in a given target cell is not constant. It may vary leukemia and non-Hodgkin's lymphoma (16). This abnormality under the influence of several factors, as reviewed elsewhere was associated with HLA antigens of the ÃŸand C loci. These (18, 45), and in particular as a function of the extracellular results, together with the indications suggesting that GR and concentration of glucocorticoids (2,22,28,34,63,73). It appears steroid response may be under the control genetic influence (3, that the patients to be investigated should be examined at 9, 29), raise the question of the possible role of transcortin in the diagnosis before any corticoid therapy. Indeed, the level of GR modulation of GR and steroid sensitivity. in the previously treated patients, even if they have been with In addition, several authors have described an increased me drawn from steroid treatment 1 to 2 weeks before, is lower than tabolism of cortisol in malignant lymphoid cells (23, 39). Others that of patients at diagnosis (5, 31). have shown a relatively higher metabolism of cortisol by B- lymphocytes than by T-lymphocytes and suggested that this Determination of Steroid Sensitivity may explain the greater resistance to cortisol of B-cells (41). It Studies performed in mouse lymphoma cell lines have dem remains to be determined whether this phenomenon may play a onstrated a fairly good correlation between the level of GR and role in the expression of GR and/or in the control of cell response. the in vitro action of steroids (40, 62). Similar investigations carried out on cells taken from patients failed to show such a References correlation, as mentioned above. Furthermore, it was demon 1. Bach, J. F. Corticosteroids. Front. Bid., 41: 21, 1975. strated that the increase in receptor levels following mitogen 2. Bealo, M., Kalimi, M., Beato, W., and Feigelson. P. Interaction of glucocorti treatment was not associated with any significant alteration of coids with rat liver nuclei: effect of adrenalectomy and cortisol administration. Endocrinology, 94: 377-387,1974. in vitro steroid effect (70). On the other hand, despite the general 3. Becker, B., Shin, D. H., Palmberg, P. F., and Wattman, S. R. HLA antigens assumption that steroid-induced cell death represents a conse and corticosteroid response. Science (Wash. D. C.), 794:1427-1428,1976. quence of the catabolic actions of the drug, there is no relation 4. Bird, C. C. Clinical classification of leukemia and lymphoma in relation to glucocorticoid therapy. In: Glucocorticoid Action and Leukemia, 7th Tenovus ship between the extent of cell lysis and the metabolic inhibition Workshop, p. 123. Cardiff, Wales: Alpha Omega Publishing, Ltd., 1979. (34, 59). It should, however, be noted that the in vitro inhibitory 5. Bloomfield, C. D., Smith, K. A., Hildebrandt, L., Zaleskas, J., Gajl-Peczalska, K. J., FrizzerÃ , G., Peterson, B. A., Kersey, J. H., Crabtree, G. R., and Munck, action of glucocorticoids was more marked in lymphoid popula A. The therapeutic utility of glucocorticoid receptor studies in non-Hodgkin's tions characterized by a high level of proliferative activity (32, 33, malignant lymphoma. In: S. lacobelli, R. J. B. King, H. R. Lindner, and M. E. 35). Lippman (eds.), Hormones and Cancer, p. 345. New York: Raven Press, 1980. 6. Bloomfield, C. D., Smith, K. A., Peterson, B. A., Cajl-Peczalska, K. J., and Recent investigations have also shown that the in vitro action Munck, A. U. In vitro glucocorticoid studies in human lymphoma: clinical and of steroids on lymphoid cells may be more complex than previ biological significance. J. Steroid Biochem., 15: 275-284, 1981.

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Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1984 American Association for Cancer Research. Glucocorticoid Receptors and Steroid Sensitivity in Normal and Neoplastic Human Lymphoid Tissues: A Review

Françoise Homo-Delarche

Cancer Res 1984;44:431-437.

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