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Publications and source records attributed to F Labrie.
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PURPOSE: The aim of the present study is to investigate whether combined androgen blockade associated with radiation therapy for localized prostate cancer decreases at 12 and 24 months the rate of positive follow-up biopsies and serum PSA compared to radiation therapy alone. This is the report of an interim analysis. METHODS AND MATERIALS: One hundred and twenty patients with clinical Stage B1-T2a, B2-T2b/T2c, and C-T3/T4, adenocarcinoma of the prostate were entered in a prospective randomized study. After written informed consent, the subjects were randomly allocated between external beam radiation therapy (EBRT) alone (group 1), 3 months of neoadjuvant combination therapy (LHRH-agonist + Flutamide) prior to EBRT (group 2), and a third group receiving combination therapy 3 months before, during, and 6 months after EBRT. There is no significant difference between the three groups concerning age, stage of disease, grade of tumor, and pretreatment PSA levels. Control transrectal ultrasound (TRUS)-guided needle biopsies (one core was taken from the initial cancer site regardless of the presence or absence of TRUS abnormalities) were done 12 and 24 months after the end of EBRT. Serum PSA measurements were done on schedule visits. RESULTS: Ninety-two and 68 patients underwent biopsies at 12 and 24 months, respectively, after the end of radiation therapy. While 62% of control patients at 12 months in Group 1 disclosed residual neoplasm, only 30% and 4% showed residual disease in groups 2 and 3, respectively (p = 0.00005). When looking at 24 months, 65, 28, and 5% showed residual cancer for groups 1, 2, and 3, respectively (p = 0.00001). The PSA measurements indicate also at 12 months a difference between the three groups (p < 0.0001), except at 24 months, the difference between the group 2 and 3 is no longer significant. CONCLUSION: The preliminary analysis of this clinical trial indicates that patients treated with radiation therapy alone show a significantly higher rate of positive biopsies at 12 and 24 months after the end of radiation therapy as compared with those treated with total antiandrogen blockade (TAB) and radiation therapy. When analyzing the median PSA serum levels, we found the same advantage at 12 months, but, at the time of the analysis at 24 months, the PSA levels are not different between groups 2 and 3.
17 beta-Hydroxysteroid dehydrogenase (17 beta-HSD) controls the last step in the formation of all androgens and all estrogens. This crucial role of 17 beta-HSD is performed by at least five 17 beta-HSD isoenzymes having individual cell-specific expression, substrate specificity, regulation mechanisms, and reductive or oxidative catalytic activity. Both estrogenic and androgenic 17 beta-HSD activities were found in all 25 rhesus monkey and 15 human peripheral intracrine tissues examined. Type 1 17 beta-HSD is a protein of 327 amino acids catalyzing the formation of 17 beta-estradiol from estrone. Its x-ray structure was the first to be determined among mammalian steroidogenic enzymes. Initially crystallized with NAD, the crystal structure of type 1 17 beta-HSD has just been determined as a complex with 17 beta-estradiol, thereby illustrating the conformation of the substrate-binding site. Type 2 17 beta-HSD degrades 17 beta-estradiol into estrone and testosterone into androstenedione, and type 4 17 beta-HSD mainly degrades 17 beta-estradiol into estrone and androst-5-ene-3 beta, 17 beta-diol into dehydroepiandrosterone. Types 3 and 5 17 beta-HSD, on the other hand, catalyze the formation of testosterone from androstenedione in the testis and peripheral tissues, respectively. The various types of human 17 beta-HSD, because of their tissue-specific expression and substrate specificity, provide each peripheral cell with the necessary mechanisms to control the level of intracellular androgens and/or estrogens, a new area of hormonal control that we call intracrinology.
OBJECTIVES: A combination of flutamide (Eulexin) or nilutamide (Anandron) with a luteinizing hormone-releasing hormone (LHRH) agonist or orchiectomy is the only therapy demonstrated to prolong life in prostate cancer. Recently, the low 50-mg daily dose of Casodex, an analogue of the pure antiandrogen flutamide, was chosen for clinical studies on the basis that the compound was 5 to 10 times more potent than flutamide, as suggested by data obtained in the inappropriate intact rat model. The present study was designed to compare the in vitro antiandrogenic activity of OH-flutamide (OH-FLU), the active metabolite of flutamide, Casodex, and nilutamide. METHODS: The effect of the antiandrogens was tested on two androgen-sensitive parameters, namely proliferation of the SEM-107 clone of Shionogi mouse mammary tumor cells and secretion of the GCDFP-15 (gross cystic disease fluid protein 15 kDa) in T-47D and ZR-75-1 human breast cancer cells. RESULTS: The twofold stimulation of Shionogi cell proliferation caused by a 10-day exposure to 1 nM testosterone was competitively reversed by incubation with OH-FLU, Casodex, or nilutamide, at the respective IC50 values of 72, 243, and 412 nM. Moreover, the marked increase in GCDFP-15 release induced by 1 nM testosterone was blocked by OH-FLU. Casodex, or nilutamide at respective IC50 values of 29, 180, and 87 nM in T-47D cells and at 35, 142, and 75 nM in ZR-75-1 cells. Similar data were detected in 4-androstenedione-induced Shionogi cell proliferation and in dihydrotestosterone-induced GCDFP-15 secretion in T-47D cells. CONCLUSIONS: OH-FLU is 3.1- to 7.8-fold more potent than Casodex, as measured on two in vitro androgen-sensitive parameters, in agreement with our recent in vivo data obtained in the model of castrated rats supplemented with 4-androstenedione implants, in which threefold greater potency of flutamide was observed. The present data, as well as other data from the literature, strongly indicate the need to choose a more appropriate dose of Casodex for the treatment of prostate cancer.
OBJECTIVE: To assess the effect of neoadjuvant combination therapy with the antiandrogen flutamide and a luteinizing-hormone-releasing hormone (LHRH) agonist administered for 3 months before radical prostatectomy, compared with surgery alone in early stage prostate cancer on histopathologic findings at surgery and serum prostate-specific antigen (PSA). METHODS: A sample of 161 randomly screened patients diagnosed as having stage B (134 patients) or C (27 patients) prostate cancer were randomly assigned to radical prostatectomy alone or to 3 months of neoadjuvant combination therapy with the antiandrogen flutamide and an LHRH agonist before radical prostatectomy. RESULTS: Neoadjuvant combination therapy before radical prostatectomy decreased cancer-positive surgical margins from 33.8% in the control group to only 7.8%, thus leaving 92.2% of patients with negative margins at surgery. A net 54% improvement of staging was observed in favor of combination therapy. Organ-confined disease, on the other hand, increased from 49.3% to 77.8% of patients after 3 months of combination therapy, for a 57.8% increase in the incidence of organ-confined disease. No cancer was found in 6 (6.7%) prostatectomy specimens from the treated group. A close correlation was found between serum PSA at diagnosis and the stage of the disease at surgery. Upstaging increased from 30% at serum PSA values of 0 to 3.0 ng/mL up to 100% at serum PSA values above 15 ng/mL. CONCLUSIONS: Although long-term follow-up of these patients is required to determine the impact on survival, the marked influence of neoadjuvant combination therapy on the stage of the disease suggests the possibility of a major improvement in the morbidity and mortality from prostate cancer.
A series of 17 beta-(N-ureylene-N,N'-disubstituted)-4-azasteroids as inhibitors of human type I 5 alpha-reductase (5 alpha-Re) were prepared from 17 beta-N-alkyl-4-methyl-4-aza-5 alpha-androstan-3-ones and various isocyanates. For the measurement of 5 alpha-Re activity, 293 cells transfected with human type I 5 alpha-Re, cDNA were used. Azasteroids with an N-cyclopropyl ring exhibited potent inhibitory activity against type I 5 alpha-Re. As the chain length increased, from the N'-ethyl to the N'-butyl chain, activity of compounds also increased and azasteroids with the N'-butyl chain showed strong inhibitory activity (IC50 = 5.3 nM). Branching of alkyl chains decreased the potency of compounds. Introduction of the 1,2-double bond significantly reduced the activity of azasteroids. Replacement of the N'-alkyl chain with the phenyl moiety gave the most active compound of this series (IC50 = 1.3 nM). Other variations such as the replacement of a N-cyclopropyl ring with the N-methyl or the N-butyl chain decreased the activity of compounds (compounds were less active compared with above). The IC50 values of N-methyl-N'-cyclohexyl- and N-butyl-N'-phenyl-ureylenes were 31.5 and 11.5 nM. respectively. In general, all azasteroids were poor inhibitors of Type II 5 alpha-Re.
The present study investigated the effect of dehydroepiandrosterone (DHEA) on bone mass and serum lipids in the rat with dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma. The animals received DHEA once daily, percutaneously, at the dose of 5, 10, or 20 mg for 9 months following a single dose of 20 mg DMBA at 50-52 days of age. Bone mineral content (BMC) and bone mineral density (BMD) of total skeleton, lumbar spine, and femur were measured by dual energy x-ray absorptiometry. A 9-month treatment with DHEA increased BMC and BMD of total skeleton by 14.2% to 14.5% (all P < 0.01) and 6.7% to 8.3% (all P < 0.01), respectively. Similarly, femoral BMC and BMD were stimulated by 13.6% to 14.7% (all P < 0.05) and by 8.1% to 9.5% (all P < 0.01), respectively. In addition, BMD of lumbar spine was increased by 10.4% to 10.8% (all P < 0.05), whereas the 9.4% to 11.1% increment in BMC of lumbar spine was not statistically significant. Treatment with DHEA led to 26% (NS), 60% (P < 0.01), and 62% (P < 0.01) decreases in serum triglyceride levels at the same doses. On the other hand, no significant change in serum cholesterol concentrations was observed. Two hundred and seventy-nine days after DMBA administration, the incidence of mammary carcinoma had decreased from 95% in control animals to 73% (P < 0.05), 57% (P < 0.01), and 38% (P < 0.01) at the daily percutaneous doses of 5, 10, and 20 mg of DHEA, respectively. Moreover, the mean tumor number per tumor-bearing animal and the mean tumor area per tumor-bearing animal were also reduced by the same treatments. DHEA increased serum total alkaline phosphatase activity and decreased urinary calcium excretion, but had no effect on the urinary ratio of hydroxyproline to creatinine and urinary phosphorus excretion. These data show that DHEA exerts a stimulatory effect on bone mass and an inhibitory effect on serum triglycerides, as well as a preventive effect on the development of mammary carcinoma induced by DMBA in the rat. Such data suggest that while decreasing the risk of breast cancer, DHEA replacement therapy could also exert beneficial effects on the bone and lipid metabolism in women receiving DHEA replacement therapy.
Plasma levels of androstane-3alpha,17beta-diol glucuronide (3alpha-DIOL-G) and androsterone glucuronide (ADT-G) as well as testosterone and adrenal C19 steroid concentrations were measured in a sample of 80 men in whom visceral adipose tissue (AT) accumulation was also determined by computed tomography. Plasma 3alpha-DIOL-G concentrations showed significant positive correlations with total body fat mass (r = 0.31; P < 0.05) and percent body fat (r = 0.28; P < 0.05). Furthermore, plasma 3alpha-DIOL-G levels were significantly associated with visceral adipose tissue accumulation (r = 0.41; P < 0.0005) as well as fasting plasma insulin (r = 0.35; P < 0.005) and glycemic and insulinemic responses to an oral glucose load (r = 0.39; P < 0.0005 and r = 0.32; P < 0.005, respectively). However, associations between 3alpha-DIOL-G and plasma glucose-insulin homeostasis indexes were no longer significant after adjustment for visceral AT area. ADT-G levels were not significantly associated with any of the adiposity variables. Subjects matched for abdominal sc AT area but with either low or high levels of visceral AT area showed significant differences in 3alpha-DIOL-G concentrations (P < 0.05), whereas subjects with low or high levels of abdominal sc AT but similar levels of visceral AT had similar 3alpha-DIOL-G concentrations. Among men with high testosterone levels, subjects with reduced 3alpha-DIOL-G concentrations had lower visceral adipose tissue accumulation than subjects with increased 3alpha-DIOL-G levels. The present results indicate that plasma 3alpha-DIOL-G, but not ADT-G, is a steroid correlate of visceral obesity. Excess visceral adipose tissue and/or concomitant alterations in insulin levels or in vivo insulin action could be responsible for the increased 3alpha-DIOL-G formation observed in this condition.
The present data show a dramatic decline in the circulating levels of dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEA-S), androst-5-ene-3 beta,17 beta-diol (5-diol), 5-diol-sulfate, 5-diol-fatty acid esters, and androstenedione in both men and women between the ages of 20-80 yr. In the 50- to 60-yr-old group, serum DHEA decreased by 74% and 70% from its peak values in 20- to 30-yr-old men and women, respectively. the serum concentrations of the conjugated metabolites of dihydrotestosterone (DHT), namely androsterone (ADT)-G, androstane-3 alpha,17 beta-diol (3 alpha-diol-G), androstane-3 beta,17 beta-diol (3 beta-diol-G), and ADT-sulfate are the most reliable parameters of the total androgen pool in both men and women, whereas serum testosterone and DHT can be used as markers of testicular secretion in men and interstitial ovarian secretion in women. The serum concentration of these various conjugated androgen metabolites decreased by 40.8% to 72.8% between the 20- to 30-yr-old and 70- to 80-yr-old age groups in men and women, respectively, thus suggesting a parallel decrease in the total androgen pool with age. As estimated by measurement of the circulating levels of these conjugated metabolites of DHT, it is noteworthy that women produce approximately 66% of the total androgens found in men. In women, most of these androgens originate from the transformation of DHEA and DHEA-S into testosterone and DHT in peripheral intracrine tissues, whereas in men the testes and DHEA and DHEA-S provide approximately equal amounts of androgens at the age of 50-60 yr. An additional potentially highly significant observation is that the majority of the marked decline in circulating adrenal C19 steroids and their resulting androgen metabolites takes place between the age groups of 20- to 30-yr olds and 50- to 60-yr-olds, with smaller changes are observed after the age of 60 yr.
This study analyzes in detail the serum concentration of the active androgens and estrogens, as well as a series of free and conjugated forms of their precursors and metabolites, after daily application for 2 weeks of 10 mL 20% dehydroepiandrosterone (DHEA) solution on the skin to avoid first passage through the liver. In men, DHEA administration caused 175%, 90%, 200% and 120% increases in the circulating levels of DHEA and its sulfate (DHEA-S), DHEA-fatty acid esters, and androst-5-ene-3 beta,17 beta-diol, respectively, with a return to basal values 7 days after cessation of the 14-day treatment. Serum androstenedione increased by approximately 80%, whereas serum testosterone and dihydrotestosterone (DHT) remained unchanged. In parallel with the changes in serum DHEA, the concentrations of the conjugated metabolites of DHT, namely androsterone glucuronide, androstane-3 alpha,17 beta-diol-G, and androstane-3 beta,17 beta-diol-G increased by about 75%, 50%, and 75%, respectively, whereas androsterone-sulfate increased 115%. No consistent change was observed in serum estrone (E1) or estradiol (E2) in men receiving DHEA, whereas serum E1-sulfate and E2-sulfate were slightly and inconsistently increased by about 20%, and serum cortisol and aldosterone concentrations were unaffected by DHEA administration. Almost superimposable results were obtained in women for most steroids except testosterone, which was about 50% increased during DHEA treatment. This increase corresponded to about 0.8 nM testosterone, an effect undetectable in men because they already have much higher (approximately 15 nM) basal testosterone levels. In women, the serum levels of the conjugated metabolites of DHT, namely androsterone glucuronide, androstane-3 alpha,17 beta-diol-G, androstane-3 beta,17 beta-diol-G, and androsterone-sulfate were increased by 125%, 140%, 120% and 150%, respectively. The present study demonstrates that the serum concentrations of testosterone, DHT, E1, and E2 are poor indicators of total androgenic and estrogenic activity. However, the esterified metabolites of DHT appear as reliable markers of the total androgen pool, because they directly reflect the intracrine formation of androgens in the tissues possessing the steroidogenic enzymes required to transform the inactive precursors DHEA and DHEA-S into DHT. As well demonstrated in women, who synthesize almost all their androgens from DHEA and DHEA-S, supplementation with physiological amounts of exogeneous DHEA permits the biosynthesis of androgens limited to the appropriate target tissues without leakage of significant amounts of active androgens into the circulation. This local or intracrine biosynthesis and action of androgens eliminates the inappropriate exposure of other tissues to androgens and thus minimizes the risks of undesirable masculinizing or other androgen-related side effects of DHEA.
Estrogen receptor beta (ER beta) is a novel steroid receptor that is expressed in rat prostate and ovary. We have cloned the mouse homolog of ER beta and mapped the gene, designated Estrb, to the central region of chromosome 12. The cDNA encodes a protein of 485 amino acids that shares, respectively, 97% and 60% identity with the DNA- and ligand-binding domains of mouse (m) ER alpha. Mouse ER beta bind to an inverted repeat spaced by three nucleotides in a gel mobility shift assay and transactivates promoters containing synthetic or natural estrogen response elements in an estradiol (E2)-dependent manner. Scatchard analysis indicates that mER beta has slightly lower affinity for E2 [dissociation constant (Kd) = 0.5 nM] when compared with mER alpha (Kd = 0.2 nM). Antiestrogens, including 4-hydroxytamoxifen (OHT), ICI 182,780, and a novel compound, EM-800, inhibit E2-dependent transactivation efficiently. However, while OHT displays partial agonistic activity with ER alpha on a basal promoter linked to estrogen response elements in Cos-1 cells, this effect is not observed with mER beta. Cotransfection of mER beta and H-RasV12 causes enhanced activation in the presence of E2. Mutagenesis of a serine residue (position 60), located within a mitogen-activated protein kinase consensus phosphorylation site abolishes the stimulatory effect of Ras, suggesting that the activity of mER beta is also regulated by the mitogen-activated protein kinase pathway. Surprisingly, the coactivator SRC-1 up-regulates mER beta transactivation both in the absence and presence of E2, and in vitro interaction between SRC-1 and the ER beta ligand-binding domain is enhanced by E2. Moreover, the ligand-independent stimulatory effect of SRC-1 on ER beta transcriptional activity is abolished by ICI 182,780, but not by OHT. Our results demonstrate that while ER beta shares many of the functional characteristics of ER alpha, the molecular mechanisms regulating the transcriptional activity of mER beta may be distinct from those of ER alpha.
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We have isolated, by screening a lambda gt11 human prostatic cDNA library, a cDNA clone that shows after transfection into transformed human embryonal kidney (293) cells high 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) activity that catalyzes efficiently the transformation of dihydrotestosterone to 5 alpha-androstane-3 alpha, 17 beta-diol. Chronologically, we name this enzyme type 3 3 alpha-HSD (3 alpha-HSD3). Surprisingly, human 3 alpha-HSD3 shares much higher amino acids sequence identity with human 20 alpha-HSD (97.8%) than with human type 1 and type 2 3 alpha-HSD (81.1 and 85.7% identity, respectively). DNA analysis predicts a protein of 323 amino acids with a molecular mass of 36,844. Alignment of the amino acid sequence of 3 alpha-HSD3 with other related 3 alpha- and 20 alpha-HSDs indicates that 3 alpha-HSD3 shares 68.1, 78.3, and 67.4% identity with rat 3 alpha-HSD and rabbit and rat 20 alpha-HSD, respectively. 3 alpha-HSD3 belongs to the aldo-keto reductase family and like almost all the members of this family preferred NADPH as cofactor.
Polyamine transport is strongly induced by insulin and estradiol (E2) in ZR-75-1 human breast cancer cells. Because signal transduction mechanisms of insulin and interleukin-4 (IL-4) partly overlap, we have compared the ability of these agents as well as that of interleukin-13 (IL-13), a cytokine that often mimics IL-4, to modulate spermidine transport in these cells. In the presence of E2, insulin increased DNA content and the rate of [3H]spermidine uptake by 2.1- and 3.7-fold, respectively, after an 8-day incubation, whereas the sole addition of IL-4 caused a quantitatively similar induction of [3H]spermidine uptake while leaving cell growth unaffected. No comparable induction of spermidine transport was observed with interleukins-1 alpha and -6, and the effect of IL-4 was not additive to that elicited by insulin plus E2. IL-4 and IL-13 stimulated [3H]spermidine uptake to a comparable extent, with half-maximal effects observed at 80 and 400 pg/ml, respectively. Interferon-gamma inhibited IL-4- and IL-13-dependent spermidine uptake to a much greater extent than basal or insulin-induced transport of the polyamine. IL-4 and IL-13 increased the Vmax and K(m) of [3H]spermidine uptake by about 4- and 2.5-fold, respectively. Na(+)-dependent amino acid uptake was increased by insulin but not by IL-4 or IL-13, indicating that the cytokines do not induce a general increase in membrane transport activity. IL-4 and IL-13 did not interfere with feedback inhibition of polyamine uptake, and only modestly decreased polyamine content after prolonged incubation, suggesting that these cytokines stimulate spermidine uptake by increasing total transport capacity rather than by repressing and endogenous inhibitor.
Human breast carcinomas are frequently infiltrated by inflammatory cells secreting several cytokines which may regulate the activity of both immune cells and neoplastic cells. The present study was designed to examine the potential action of interleukin-4 (IL-4) and interleukin-13 (IL-13) in human breast cancer cells. Exposure of ZR-75-1 breast cancer cells to IL-4 or IL-13 for 10 days decreased the amplitude of the mitogenic action of 17 beta-estradiol by 75% and 55%, respectively, while these cytokines failed to change basal cell proliferation. These cytokines also exerted a similar action in T-47D cells. Exposure to IL-4 or IL-13 markedly increased gross cystic disease fluid protein-15 (GCDFP-15) release in both ZR-75-1 and T-47D cells. The half-maximal stimulatory effects of IL-4 and IL-13 on GCDFP-15 secretion were exerted at respective values of 16 +/- 3 pM and 91 +/- 8 pM in T-47D cells incubated for a period of 10 days. The effect of IL-13 was not additive to that elicited by IL-4, whereas the stimulation of GCDFP-15 release by these interleukins were additive to that exerted by maximally effective concentrations of the androgen dihydrotestosterone and the synthetic glucocorticoid dexamethasone. Furthermore, exposure of ZR-75-1 cells of IL-4 and IL-13 increased GCDFP-15 mRNA levels by 5.5- and 6.0-fold, respectively. The present results demonstrate that IL-4 and IL-13 may decrease estrogen-induced breast cancer cell proliferation and induce the expression of a breast cancer marker, thus strongly suggesting that breast cancer cells are targets of both IL-4 and IL-13 action.
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Primer extension analysis reveals the presence of different forms of mRNA species for rat type I 5 alpha-reductase. Using a 5 alpha-reductase cDNA probe to screen the rat liver lambda gt11 cDNA library, we isolated cDNA clones that have 4 additional amino acids in the NH2-terminal region as compared with the previously reported sequence for rat type I 5 alpha-reductase. These four additional amino acids elongate the rat type I 5 alpha-reductase amino acid sequence to 259 amino acids, the same number as in human type I 5 alpha-reductase, with which it shares 60% identity. Expression of the long and short rat type I 5 alpha-reductase by transfection in human adrenal adenocarcinoma cells, SW-13 cells, indicated that the long cDNA encoded a protein with a higher affinity for the substrate than the short cDNA. To determine the effect of pituitary hormones and dihydrotestosterone (DHT), the mRNA levels in the livers of rats treated with pituitary implants, hypophysectomized, castrated, and castrated coupled with DHT treatment were quantified by dot-blot hybridization assay using rat type I 5 alpha-reductase cDNA as probes. The results demonstrated that rat type I 5 alpha-reductase mRNA is stimulated by pituitary hormones and castration but is decreased by DHT and hypophysectomy.
Modulation of androgen receptor (AR) expression during neoadjuvant endocrine therapy in human prostates of patients with localized prostate cancer was investigated by immunohistochemistry. In 8 of 15 untreated prostatectomy specimens, the majority of prostatic glandular cells displayed nuclear immunostaining for AR, whereas only 1 of 26 pretreated cases displayed a similar glandular AR expression. Expression of AR in the prostatic stromal compartment of nontreated cases proved to be quite heterogeneous, since 4 of the 15 (27%) examined specimens did not show stromal AR expression. After preoperative neoadjuvant therapy, this value was 68%, although this difference did not reach statistical significance. Prostatectomy specimens of the treated patients contained carcinomas with a higher Gleason score than those of untreated patients. AR expression in carcinomas of treated patients was diminished (P= 0.05), which may be attributed to their relatively lower differentiation grade. The data strongly suggest that neoadjuvant hormone therapy reduces AR expression by nonneoplastic prostatic glandular cells and carcinoma cells by a selective, but incomplete, elimination of AR-positive cells.