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W R Fair

Publications and source records attributed to W R Fair.

At least 73 records · Page 4Linked to original sources
PubMed1997

Evaluation of the telomeric repeat amplification protocol (TRAP) assay for telomerase as a diagnostic modality in recurrent bladder cancer.

There is a need for the identification of an accurate test for the detection of recurrent bladder cancer. In this study, we evaluate the telomeric repeat amplification protocol (TRAP) assay for detection of telomerase as a potential new method for bladder cancer detection and compare it to voided urine cytology. A urine sample and a bladder wash were obtained from 63 patients with a history of bladder cancer. Cytological evaluation was performed on voided urine, and the TRAP assay was performed on voided urine and bladder wash. The overall clinical sensitivity of the TRAP assay, as defined by the ability to identify correctly the patients with pathologically confirmed bladder cancer, was 35% in voided urine and 50% in bladder wash, whereas the overall clinical sensitivity of voided urine cytology was 71%. The sensitivity of voided urine cytology for the papillary and noninvasive tumors (Ta) was 50%, compared to 92% for the superficially invasive tumors (T1), 62% for the muscle-invasive tumors (T2+), and 100% for the high-grade flat carcinoma in situ (Tis). The clinical sensitivity of the TRAP assay using voided urine was 46% for Ta, 50% for T1, 18% for T2+, and 20% for Tis. The sensitivity of the TRAP assay in Ta disease was similar to that of cytology (50% for cytology versus 46% for the TRAP assay). There was a strong association between the total number of exfoliated malignant cells and the sensitivity of the assay. The sensitivity of the TRAP assay in bladder washes was 44% for Ta, 67% for T1, 46% for T2+, and 43% for Tis. The TRAP assay is reproducible, highly specific, and not dependent on the expertise of the cytopathologist. These results suggest that this assay should be further investigated as a diagnostic tool for bladder cancer.

Carcinoma, Papillary↗
PubMed1996

Overexpression of protein kinase C-zeta (PKC-zeta) inhibits invasive and metastatic abilities of Dunning R-3327 MAT-LyLu rat prostate cancer cells.

Previously, we reported that protein kinase C (PKC)-zeta mRNA levels are reduced markedly in metastatic Dunning R-3327 rat prostate tumors relative to the nonmetastatic Dunning H tumor and normal rat prostate (C.T. Powell et al., Cell Growth & Differ., 5: 143-149, 1994). To examine the effect of PKC-zeta on metastatic and invasive abilities of an aggressive Dunning R-3327 cell line, we generated stably transfected clones of MAT-LyLu cells that overexpress active PKC-zeta. PKC-zeta-overexpressing MAT-LyLu cells exhibited tumorigenicity and growth rates in syngeneic rats similar to those of MAT-LyLu cells transfected with vector alone or untransfected MAT-LyLu. However, nine independent clones of PKC-zeta-expressing cells exhibited an average 2-fold lower tendency to metastasize to lungs relative to vector-transfected MAT-LyLu cell clones, with about 2-fold and 4.5-fold fewer metastases per rat in two separate protocols. In addition, the ability of four PKC-zeta overexpressing MAT-LyLu clones to invade through Matrigel in a Boyden chamber assay was reduced an average of 12-fold relative to three vector-transfected clones. These results indicate that increased PKC-zeta expression can substantially suppress invasion and metastasis by an aggressive rat prostate tumor.

Animals↗
PubMed1996

Prostate cancer: emerging concepts. Part II.

OBJECTIVE: To review important topics related to prostate cancer that have arisen since this subject was last covered in Annals in 1993. The review consists of two parts. Part II describes neoadjuvant hormonal therapy, new local treatment options (including three-dimensional conformal radiation therapy, brachytherapy, and cryosurgery), antiandrogen therapy management of erectile dysfunction, funding and legislation for research, and areas for future research, especially in genetics investigations. STUDY SELECTION: Randomized studies identified through a MEDLINE search (1992 to 1996); large, single-institutional conferences and consortiums; and studies presented at regional, national, and international symposia. DATA SYNTHESIS: Qualitative and quantitative data are reported. Part II describes results of completed randomized trials that used neoadjuvant hormonal therapy. Studies have shown that nearly 50% more patients with cT2 disease will have pathologically confined (pT2) prostate cancer as a result of preoperative neoadjuvant hormonal therapy. Time to development of progressive disease and disease-free survival are improved in patients receiving neoadjuvant hormonal therapy before radiation therapy, but the long-term overall effects on survival of neoadjuvant therapy before surgery or radiation are unknown. Other methods for treating localized prostate cancer (three-dimensional conformal radiation therapy, brachytherapy, and cryotherapy) are gaining popularity, despite the lack of long-term efficacy results. Advances in the understanding of the optimal use of antiandrogens and managing treatment-induced erectile dysfunction continue to benefit patients with prostate cancer. CONCLUSIONS: Prostate cancer is being detected with increasing frequency, and many patients are receiving such treatments as radical prostatectomy and radiation therapy. Although refinements in prostate-specific antigen (PSA)-based testing have contributed substantially to the increased rate of detection of prostate cancer, the incidence of disease was increasing dramatically even before PSA detection was possible. Despite earlier detection, the optimal therapy for the early form of the disease is still enigmatic. Further studies and longer follow-up of patients who participated in completed studies are needed to better define the outcomes and importance of prostate cancer therapies. More research is needed to help elucidate the reasons for the increased incidence of the disease; such efforts should help define strategies to ultimately prevent prostate cancer.

Androgen Antagonists↗
PubMed1996

Prostate cancer: emerging concepts. Part I.

OBJECTIVE: To review important topics related to prostate cancer that have arisen since this subject was last covered in Annals in 1993. The review consists of two parts, Part I describes advances in prostate-specific antigen (PSA) interpretation (including PSA density and velocity, age-specific reference ranges, "free" and "bound" PSA ratios, the utility of PSA in defining the pathologic extent of prostate cancer, and the use of these concepts in helping define appropriate treatment strategies), the management of patients with organ-confined prostate cancer, and pathologic interpretation of prostatectomy specimens. STUDY SELECTION: Randomized studies identified through a MEDLINE search (1992 to 1996); large, single-institution conferences and consortiums; and studies presented at regional, national, and international symposia. DATA SYNTHESIS: Both qualitative and quantitative data are reported. Most of the data presented in part I concern advances in the interpretation of PSA results and characterization of the pathologic findings of prostatectomy specimens. Studies show that almost 50% of patients with clinically organ-confined prostate cancer have disease that is beyond the confines of the prostatic capsule. The chances of developing clinical (radiographic) and biochemical failure (that is, elevation of PSA levels) are 3% and 6%, respectively, for pathologically organ-confined cancer and 10% and 26%, respectively, for non-specimen-confined prostate cancer. Actual progression-free survival rates 10 years after radical prostatectomy are 70% for patients with organ-confined cancer and 39% for patients with cancer that has spread through the capsule. CONCLUSIONS: Prostate cancer is being detected with increasing frequency, and many patients with this condition are receiving such treatments as radical prostatectomy and radiation therapy. Although refinements in PSA-based testing have contributed substantially to the increased detection rate of prostate cancer, the incidence of disease was increasing dramatically even before the detection of PSA was possible. Yet, despite earlier detection, the optimal therapy for the early form of the disease remains enigmatic. Further studies and longer follow-up of patients who participated in completed studies are needed to better define the outcomes of prostate cancer therapies and to help determine the importance of the therapies. Increased research efforts are necessary to help elucidate the reasons for the great increase in the incidence of the disease; such efforts should help define strategies to ultimately prevent prostate cancer.

Humans↗
PubMed1996

Microsatellite instability and deletion analysis of chromosome 10 in human prostate cancer.

Despite the clinical relevance of prostate cancer, few aspects regarding the molecular alterations involved in the process of prostate carcinogenesis are clearly understood. Cytogenetic and molecular genetic studies have identified specific abnormalities in prostate tumors, mainly on chromosomes 8, 10 and 16. On the basis of these findings, we designed a study to further characterize the altered regions on chromosome 10, using 15 microsatellite markers on a population composed of 20 paired normal and primary non-metastatic prostatic-tumor samples. Overall, 65% (13/20) of the cases analyzed showed molecular alterations, mainly rearrangements and deletions. The locus presenting the highest rate of abnormalities was D1OS221, which maps to 10q23-q24. Another region with frequent alterations was 10q21, at the DIOS109 locus. There was no statistical association between microsatellite abnormalities and Gleason grade or tumor stage in the prostate cancer cases studied. These results suggest that microsatellite alterations on the long arm of chromosome 10 are non-random events occurring in prostate cancer and that they may play a role in the process of tumorigenesis in these neoplasms.

Carcinoma↗
PubMed1996

Anti-androgenic effects of combination finasteride plus flutamide in patients with prostatic carcinoma.

OBJECTIVES: To determine the anti-androgenic effects and safety of the combination of finasteride and flutamide in men with prostate cancer. PATIENTS AND METHODS: Seventeen men with various stages of prostate cancer, all of whom were candidates for androgen deprivation therapy, were treated with finasteride plus flutamide and were followed for a mean of 13.6 months using measurements of serum prostate specific antigen (PSA), and an assessment of regression and side-effects. RESULTS: The initial median PSA level was 19.8 ng/mL: at 3, 6 and 12 months the median PSA had fallen to 1.2, 0.85 and 0.8 ng/mL, respectively. In four patients followed for 2 years, the anti-neoplastic effects were sustained. Patients with initially palpable disease had regression, as assessed by a digital rectal examination. Side-effects included gynaecomastia (five patients), mildly elevated hepatic transaminases (two) and diarrhoea (one). Most men maintained their previous sexual function. CONCLUSIONS: Early results suggest that the combination of finasteride and flutamide provides significant anti-androgenic therapy and maintains sexual function in most men. A further investigation with more patients and a longer follow-up is warranted.

Aged↗
PubMed1996

Methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy and cystectomy for unresectable bladder cancer.

PURPOSE: We combined chemotherapy and surgery to improve local control and survival of patients with unresectable bladder cancer. MATERIALS AND METHODS: A total of 41 patients with unresectable bladder cancer (T4bNX/N + M0) received methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) chemotherapy followed by radical cystectomy when possible. End points were response to M-VAC, local control and survival. RESULTS: Minimum followup was 4 years (range 4 to 7). Of the 41 patients 14 (34%) achieved a complete (T0) and 27 (66%) achieved an incomplete (T+) clinical response to M-VAC, including 29 who underwent exploration and 24 who underwent cystectomy. Definitive surgery was not done in 17 patients due to lack of response to M-VAC with local or systemic tumor progression, or refusal. Nine patients (22%) are alive, including all but 1 after cystectomy for T0 disease, and 2 had T+ tumor confined to the bladder for longer than 5 years. None of the patients with no response or tumor progression on M-VAC survived. Resection of extravesical disease after M-VAC in 16 patients did not prolong survival or improve local tumor control. Six patients required laparotomy for palliation of tumor related complications. CONCLUSIONS: Our results suggest that patients who present with unresectable bladder cancer may benefit from M-VAC and definitive surgery, especially when disease is T0 and P0 status. Surgery may salvage select cases of advanced pelvic tumor down staged by chemotherapy to tumors pathologically confined to the bladder. Alternative treatment strategies are needed for the majority of patients with locally advanced bladder cancer.

Adult↗
PubMed1996

Overexpression of p53 protein in a high-risk population of patients with superficial bladder cancer before and after bacillus Calmette-Guérin therapy: correlation to clinical outcome.

PURPOSE: We have previously demonstrated that p53 overexpression is predictive of disease progression and survival in Ta, Tis, and T1 tumors. Instillation of Bacillus Calmette-Guérin (BCG) is now accepted to be the most efficient adjuvant therapy for superficial bladder carcinoma. The aim of this study was to determine if p53 status, assessed before and after intravesical BCG therapy, can predict clinical outcome in a high-risk population of patients with superficial bladder carcinoma. MATERIALS AND METHODS: We examined 196 tissue specimens from 98 patients, obtained immediately before and after intravesical BCG therapy. The pretherapy population was composed of 22 Ta, 57 Tis, and 19 T1 tumors. After BCG, 66 specimens were TO and 32 had residual tumors. Nuclear p53 overexpression was analyzed in relation to time to disease progression and disease-specific survival. RESULTS: The median follow-up duration was 44 months. The detection of nuclear p53 overexpression before BCG therapy did not predict response to BCG therapy. Pre-BCG p53 protein overexpression, response to BCG therapy, and pre-BCG stage were all independent markers of disease progression. In patients with residual disease after BCG therapy (nonresponders), multivariate analysis confirmed that posttherapy p53 overexpression was the only independent marker of disease progression. CONCLUSION: In this high-risk population of patients with superficial bladder tumors, patients who have p53 nuclear overexpression in the tumor and stage T1 disease before BCG therapy are at high risk of disease progression. Furthermore, in the group of patients with residual disease after BCG therapy, p53 status is a better predictor of disease progression than post-BCG stage.

Administration, Intravesical↗
PubMed1996

Simultaneous retroperitoneal, thoracic, and cervical resection of postchemotherapy residual masses in patients with metastatic nonseminomatous germ cell tumors of the testis.

PURPOSE: We report our experience with simultaneous resection of residual masses above and below the diaphragm in patients with metastatic nomseminomatous germ cell tumor (NSGCT) of the testis. MATERIALS AND METHODS: Twenty-four patients underwent simultaneous resection of residual postchemotherapy masses in the retroperitoneum and chest, including three who also had radical neck dissection. All had been heavily pretreated with chemotherapy and five had undergone previous retroperitoneal lymph node dissections (RPLNDs). RESULTS: The combined procedure was performed with no mortality and low morbidity. The median length of the procedure was 5 hours 45 minutes, median blood loss 500 mL, and median length of hospital stay 9 days. Complications included one patient with chylous ascites and one with a prolonged air leak, both of which resolved with conservative management. Eighteen patients had similar pathologic findings in all sites: 13 with necrosis only and five with teratoma only. Six patients had discordant pathology in the abdomen and chest, including one with viable tumor in the chest only and two with viable tumor in the abdomen only. The overall actuarial 5-year survival rate for all patients was 79%. CONCLUSION: Simultaneous resection of neck, chest, and abdominal residual masses after chemotherapy for germ cell tumors is both a feasible and safe alternative to staged excision in selected patients who require surgical intervention at multiple sites and fulfills the objective of rendering patients disease-free in a single operative procedure.

Adolescent↗
PubMed1996

Outcomes of initial surveillance of invasive squamous cell carcinoma of the penis and negative nodes.

PURPOSE: We determined factors predictive of inguinal nodal relapse in patients with stages T1 to 3NOMO squamous cell penile cancer treated initially with surveillance of inguinal nodes. MATERIALS AND METHODS: Between 1980 and 1994, in 42 patients with stages T1 to 3NOMO squamous cell penile cancer of 60 with invasive disease seen at our center the inguinal nodes were surveyed after definitive treatment of the primary tumor. Clinical inguinal nodal recurrences were treated with inguinal lymphadenectomy. RESULTS: A total of 26 patients (62%) had inguinal nodal recurrences during followup, with 50% occurring within 1.4 years and 75% within 2.8 years of resection of the primary tumor. The only factor predicting nodal relapse was grade of the primary tumor at initial treatment. Patients with grade 1 tumors had a 45% long-term actuarial relapse-free survival rate. All other groups had a 100% actuarial nodal relapse rate. Of the patients 10% had metastatic disease without nodal recurrence. CONCLUSIONS: Invasive penile cancer may be associated with inguinal lymph node and hematogenous metastasis. A strong case for prophylactic bilateral inguinal lymphadenectomy can be made in patients with primary tumors other than grade 1, since surveillance of these patients will not spare them eventual lymphadenectomy and may potentially compromise survival by delaying surgery. Patients with grade 1 tumors may be offered either careful surveillance or prophylactic bilateral inguinal lymphadenectomy depending on the clinical circumstances and patient preference.

Adult↗
PubMed1996

Persistent membrane translocation of protein kinase C alpha during 12-0-tetradecanoylphorbol-13-acetate-induced apoptosis of LNCaP human prostate cancer cells.

Others have reported that the phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA), an activator and down-regulator of most protein kinase C (PKC) isozymes, can induce apoptotic cell death of androgen-sensitive LNCaP but not androgen-insensitive PC-3 or DU 145 human prostate cancer cells. As a first step toward uncovering the mechanism by which TPA induces apoptosis of LNCaP cells, we quantified expression of PKC isozyme mRNAs in unmodified and TPA-resistant LNCaP cells and in naturally TPA-resistant PC-3, PC-3M, and DU 145 cells. All of the cell lines and normal prostate expressed RNAs for PKC alpha, delta, epsilon, eta, and mu; only DU 145 cells and normal prostate expressed PKC beta and theta RNAs, and none expressed PKC gamma. The amount of PKC alpha RNA and protein was 6- to 38-fold lower, and PKC mu RNA was 4.5- to 16.5-fold higher in unmodified and TPA-resistant LNCaP cells than in the androgen-independent cells. We examined the effects of TPA on PKC alpha and mu mRNA levels and on membrane translocation of PKC alpha. Incubation with TPA for 6 h or more induced 95% inhibition of cell growth, a transient 12-fold increase and 5-fold decrease in PKC alpha and mu mRNA levels, respectively, and prolonged translocation of PKC alpha to non-nuclear membranes in unmodified LNCaP cells and in TPA-resistant LNCaP cells from which TPA had been removed for 10 days. TPA-resistant LNCaP cells in the continuous presence of TPA, or 24 h after removal of TPA, had down-regulated PKC alpha and remained resistant to re-addition of TPA. These data demonstrate a strong correlation of the presence and absence of membrane PKC alpha with apoptosis and resistance to apoptosis, respectively.

Apoptosis↗
PubMed1996

Analysis of p21WAF1/CIP1 in primary bladder tumors.

The p21WAF1/CIP1 gene is regulated by p53 and encodes a cyclin-dependent kinase (Cdk)-inhibitor involved in senescence and cell quiescence. The role of p21 as a negative regulator of cell proliferation suggests that it may function as a tumor suppressor gene. However, only a few mutations of the p21WAF1/CIP1 gene have been reported to date. In order to assess potential p21WAF1/CIP1 gene alterations in human bladder cancer, we have examined this gene and its encoded product in a well-characterized cohort of 27 primary bladder tumors. Mobility shifts by single-strand conformation polymorphism in the p21WAF1/CIP1 gene were identified in 2 cases. Sequencing analyses revealed that one of these cases had point mutations in the 3' untranslated region, while the other case had a frame shift mutation at positions 322 (C to A) and a deletion of 8 nucleotides (323-->331; CCG-->ACG, codon 81 Arg-->Thr) that produced a stop signal at codon 83 (Gly--Stop). This tumor had a p21-negative phenotype by immunohistochemistry, but did not lose any allele. We further characterized these cases by the study of TP53 mutations using single-strand conformation polymorphism (PCR-SSCP) and sequencing, as well as immunohistochemical assays. Seven mobility shifts were identified and seven cases showed p53 nuclear accumulation. The two cases displaying mutated p21WAF1/CIP1 had wild-type TP53. It is concluded that p21WAF1/CIP1 gene aberrations are infrequent in bladder carcinoma but may be occasionally identified in primary bladder tumors.

Aged↗
PubMed1995

Decreased growth of established human prostate LNCaP tumors in nude mice fed a low-fat diet.

BACKGROUND: Geographic variation in the incidence of clinically detected prostate cancer is considerable, with a 120-fold greater incidence in the United States than in China. The incidence of latent prostate cancer, however, shows little variation worldwide, with approximately 30% of men older than age 50 years having microfocal disease (determined by autopsy). Some epidemiologic studies have suggested that a high intake of dietary fat may constitute a risk factor for the development of advanced prostate cancer. PURPOSE: We studied the influence of dietary fat content on the growth of tumors established in athymic nude mice with androgen-sensitive, human prostatic adenocarcinoma cells (LNCaP cells). We also investigated whether manipulation of dietary fat content altered prostate-specific antigen (PSA) production by these tumors. METHODS: Tumors were induced in nude mice by subcutaneous injection of 10(6) LNCaP cells. Both the American Type Culture Collection (ATCC) LNCaP cell line and a more androgen-responsive subline derived from it (i.e., the Harris LNCaP cell line) were used. Mice were fed a 40.5-kcal% fat diet at the time of tumor cell injection. Three weeks later, after measurable tumors were formed, the animals were assigned to receive diets with one of the following fat contents: 40.5, 30.8, 21.2, 11.6, or 2.3 kcal% fat. Food intake, animal weights, and tumor volumes were recorded weekly; serum PSA and testosterone levels were measured at the termination of the study. Post hoc multiple comparisons were made using the Student-Newman-Keuls procedure. Two-sided tests of statistical significance were used to evaluate pairwise comparisons. RESULTS: Tumor growth rates, final tumor weights, and ratios of final tumor weights to animal weights were substantially greater in groups that continued to receive a 40.5-kcal% fat diet than in groups whose diets were changed to 2.3 kcal%, 11.6 kcal%, or 21.2 kcal% fat (all P values < .04). Comparison of these parameters among the 2.3-kcal%, 11.6-kcal%, and 21.2-kcal% dietary fat groups did not reveal any statistically significant differences. No statistically significant differences were noted in total ingested calories, animal weight gain, serum testosterone levels, or histopathologic characteristics of the tumors among the tested dietary groups. Serum PSA levels were highest in the 40.5-kcal% fat group and lowest in the 2.3-kcal% fat group (evaluated only for ATCC LNCaP cells; P < .05). CONCLUSIONS: Reduction of dietary fat substantially slows the growth of tumors established from human prostatic adenocarcinoma cells in a murine xenograft model. A positive association persists between tumor volumes and serum PSA levels even after extreme modification of dietary fat content.

Adenocarcinoma↗
PubMed1995

Alternatively spliced variants of prostate-specific membrane antigen RNA: ratio of expression as a potential measurement of progression.

We examined expression of prostate-specific membrane antigen (PSM) mRNA in normal prostate using reverse transcription-PCR and sequencing. An alternatively spliced variant, PSM', along with the previously described PSM form, was found in normal prostate. PSM' cDNA is shorter (2387 nucleotides) than PSM (2653 nucleotides). The cDNAs are identical except for a 266-nucleotide region near the 5' end of PSM cDNA (nucleotide 114-380) that is absent from PSM'. This deleted region includes the translation initiation codon and codons for the putative transmembrane domain of PSM. Thus, PSM' RNA codes for a protein that has no apparent signal sequence. We verified the existence of spliced mRNA variants in human primary tissue specimens by RNase protection assay. In LNCaP human prostatic cancer cells and in primary prostate tumors, PSM is the dominant form. In contrast, normal human prostate expressed more PSM' than PSM. Benign prostatic hypertrophy samples showed about equal expression of both variants. We quantified the relative expression of each variant by densitometry and compiled a tumor index, which is the ratio of PSM:PSM' level. LNCaP has an index ranging from 9-11, carcinoma of the prostate from 3-6, benign prostatic hypertrophy from 0.75-1.6, and normal prostate from 0.075-0.45. The index reflects the increased expression of PSM over PSM' following the progression from normal to tumor state. This tumor index may be a useful indicator for the measurement of tumor progression. PSM and PSM' may be functionally different proteins as a result of differences in structure or cellular location. We are investigating the prevalence of one form over the other and how it may influence tumor progression.

Alternative Splicing↗
PubMed1995

Reversal by transferrin of growth-inhibitory effect of suramin on hormone-refractory human prostate cancer cells.

BACKGROUND: The second leading cause of cancer-related deaths in American men is metastatic hormone-refractory adenocarcinoma of the prostate, for which there is currently no effective treatment. Transferrin is abundant in bone stroma and has been found to stimulate models of hormone-refractory metastatic prostate cancer. Suramin, a compound that has been used to treat metastatic prostate cancer, has been demonstrated to antagonize the binding of transferrin to the transferrin receptor and to suppress uptake of iron by hematopoietic cells. PURPOSE: The purpose of our study was to determine whether transferrin may reverse the inhibitory action of suramin on metastatic prostate-derived cell lines. METHODS: Five human prostate cell lines (PC-3, PC-3M, DU-145, TSU-Pr1, and LNCaP) derived from metastatic deposits were examined for response to growth stimulation by apotransferrin, for the presence of transferrin receptors by binding of 125I-labeled transferrin, and for relative transferrin receptor messenger RNA (mRNA) content by ribonuclease protection assays. We measured the amount of growth inhibition by suramin in low serum assays to demonstrate maximal inhibition over the apotransferrin to reverse the inhibition of suramin in these tumors. RESULTS: The results clearly demonstrate that the androgen-insensitive metastatic cell lines (PC-3, PC-3M, DU-145, and TSU-Pr1) demonstrate increased cell numbers when exposed to holotransferrin or apotransferrin, while the androgen-sensitive cell line (LNCaP) did not show any increase. All cell lines demonstrated a similar number of transferrin receptors and transferrin receptor mRNA. We used these maximally inhibitory, but clinically relevant, concentrations of suramin to determine whether transferrin could reverse the inhibition, and it did, but only in the androgen-insensitive metastatic lines. Indeed, in the PC-3 cells, inhibition turned to stimulation with the addition of transferrin, and even at the highest concentration of suramin tested, 400 microM, a concentration that would be toxic to patients, the amount of inhibition by suramin was still reduced by more than 50% by transferrin in TSU-Pr1 cells. In the androgen-sensitive LNCaP cells, however, transferrin had limited ability to block the inhibitory activity of suramin. CONCLUSIONS: Concentrations of tumor-stimulating factors, such as transferrin, in the metastatic microenvironment need to be taken into consideration in the use of suramin and suramin-like derivatives. Novel strategies need to be identified that will negate the action of transferrin on androgen-insensitive cells.

Androgens↗