Stromal and epithelial expression of tumor markers hyaluronic acid and HYAL1 hyaluronidase in prostate cancer.

Hyaluronic acid (HA), a glycosaminoglycan, regulates cell adhesion and migration. Hyaluronidase (HAase), an endoglycosidase, degrades HA into small angiogenic fragments. Using an enzyme-linked immunosorbent assay-like assay, we found increased HA levels (3-8-fold) in prostate cancer (CaP) tissues when compared with normal (NAP) and benign (BPH) tissues. The majority ( approximately 75-80%) of HA in prostate tissues was found to exist in the free form. Primary CaP fibroblast and epithelial cells secreted 3-8-fold more HA than respective NAP and BPH cultures. Only CaP epithelial cells and established CaP lines secreted HAase and the secretion increased with tumor grade and metastasis. The pH activity profile and optimum (4.2; range 4.0-4.3) of CaP HAase was identical to the HYAL1-type HAase present in human serum and urine. Full-length HYAL1 transcript and splice variants were detected in CaP cells by reverse transcriptase-polymerase chain reaction, cloning, and sequencing. Immunoblotting confirmed secretion of a approximately 60-kDa HYAL1-related protein by CaP cells. Immunohistochemistry showed minimal HA and HYAL1 staining in NAP and BPH tissues. However, a stromal and epithelial pattern of HA and HYAL1 expression was observed in CaP tissues. While high HA staining was observed in tumor-associated stroma, HYAL1 staining in tumor cells increased with tumor grade and metastasis. The gel-filtration column profiles of HA species in NAP, BPH, and CaP tissues were different. While the higher molecular mass and intermediate size HA was found in all tissues, the HA fragments were found only in CaP tissues. In particular, the high-grade CaP tissues, which showed both elevated HA and HYAL1 levels, contained angiogenic HA fragments. The stromal-epithelial HA and HYAL1 expression may promote angiogenesis in CaP and may serve as prognostic markers for CaP.

MAG3-F0 scintigraphy in decision making for emergency intervention in renal colic after helical CT positive for a urolith.

UNLABELLED: Patients with renal colic are evaluated with clinical, laboratory, and imaging methods for stratification for emergency decompression, medical treatment, or discharge and follow up. The current standard practice is heavily based on unenhanced helical CT for detecting uroliths. However, the presence of a urolith does not necessarily mean that the kidney is obstructed and requires emergency decompression. In this study, technetium-mercaptoacetyltriglycine (MAG3) diuretic scintirenography was used to detect obstruction in patients with renal colic. The contribution of this test to patient management after positive findings from helical CT was also studied. METHODS: Diagnostic criteria were established on the basis of previous experience with 60 patients who had renal colic and had undergone radiography of the kidneys, ureters, and urinary bladder (KUB) and diuretic Tc-MAG3 scintirenography and were followed up to correlate scintigraphic findings with clinical outcome. Subsequently, 80 patients with renal colic underwent scintigraphy within 12 h of presentation in the emergency room, after abdominal helical CT showed findings positive for calculus and suggestive of obstruction. After therapeutic oral or intravenous hydration and analgesics, diuretic dynamic renal scintigraphy (flow, function, delayed imaging) was performed after intravenous injections of 10 mCi (370 MBq) 99mTc-MAG3 and 40 mg furosemide (at zero time, or F0). Results were available soon after completion of the study and were considered in patient management. Four characteristic patterns of scintirenography, essential in patient stratification and treatment, had been standardized and were used for interpretation of the studies: the unobstructed kidney; the partially obstructed kidney, proximally or distally obstructed, with mild to severe obstruction and impairment of function; the totally obstructed kidney, with arrested renal function; and the unobstructed but dysfunctioning kidney after decompression, or stunned kidney. RESULTS: Among the 80 patients with positive helical CT findings, 56.5% were found to have obstruction by scintigraphy (32.5% partially, 24% completely); the remaining 43.5% did not have obstruction (21% without an indication of recent obstruction and 22.5% with stunned kidneys after spontaneous decompression). Occasionally, findings of preexistent urine extravasation or infection were present. Patients who, by scintigraphy, never had obstruction or had experienced spontaneous decompression did not require admission or emergency intervention; those with complete or severe obstruction required admission and decompression for relief of pain or restoration of function, whereas those with mild obstruction were treated variably with forced fluids, analgesics, or, less frequently, elective surgery. Outcome information from clinical examination, imaging, and interventional findings indicated that this stratification was successful. The test caused no side effects. CONCLUSION: For renal colic, clinical selection, KUB radiography, and even positive helical CT findings were all found to have a low positive predictive value for obstruction (in this study, 35%, 32%, and 56% respectively). Anatomic studies, including helical CT, should be followed by diuretic MAG3-F0 scintirenography to diagnose and quantify or exclude obstruction, detect spontaneous decompression, and appropriately stratify patients for emergency intervention, observation and medical therapy, or further work-up and discharge with referral to the clinic.

HA-HAase urine test. A sensitive and specific method for detecting bladder cancer and evaluating its grade.

Hyaluronic acid and HAase are intricately associated with the biology of bladder tumor angiogenesis and metastasis. Tumor-associated HA and HAase are secreted in urine. In G2 and G3 bladder tumors, HA is degraded by HAase, resulting in the generation of angiogenic HA fragments, which, in turn, are secreted in urine. An elevated urinary HA level (> or = 500 ng/mg), indicating a positive HA test, suggests the presence of bladder cancer regardless of tumor grade. The urinary HAase levels correlate with the malignant potential of bladder cancer and are elevated (> or = 10 mU/mg) in the urine of patients with G2 and G3 bladder cancer. Combining the results from the HA and the HAase tests (the HA-HAase test) yields inferences, including the detection of bladder cancer and the evaluation of its grade. The overall 92% sensitivity of the HA-HAase test to detect bladder cancer is higher than the sensitivity of individual tests with little compromise in specificity. The HA-HAase test is equally sensitive for monitoring tumor recurrence. When compared with existing noninvasive tests, the HA-HAase test may be significantly less expensive and more accurate.

Urinary hyaluronic acid and hyaluronidase: markers for bladder cancer detection and evaluation of grade.

PURPOSE: Specific patterns of progression and frequent recurrence of bladder tumors determine the choice of treatment, frequency of surveillance, quality of life, and ultimately, patient prognosis. The prognosis would be improved if an accurate noninvasive test was available for diagnosis. Identification of markers that function in bladder cancer progression would be helpful in designing such diagnostic tests. The glycosaminoglycan, hyaluronic acid (HA), promotes tumor metastasis. Hyaluronidase (HAase), an endoglycosidase, degrades HA into small fragments that promote angiogenesis. We have previously shown that both HA and HAase are associated with bladder cancer and may function in bladder tumor angiogenesis. In this study we examined whether urinary HA and HAase levels serve as bladder cancer markers. MATERIALS AND METHODS: Among the 513 urine specimens analyzed, 261 were from transitional cell carcinoma (TCC) patients, 9 from patients with non-TCC tumors, and 243 from controls (normals, patients with other genitourinary (GU) conditions or a history of bladder cancer (HxBCa)). The urinary HA and HAase levels were measured by two ELISA-like assays that utilize a biotinylated HA binding protein for detection. These levels were normalized to total urinary protein and were expressed as ng./mg. (HA test) and mU/mg. (HAase test), respectively. RESULTS: The urinary HA levels were elevated (2.5 to 6.5 fold) in bladder cancer patients (1173.7+/-173.4; n = 261) as compared with normals (246.1+/-38.5; n = 41); GU patients (306.6+/-32.2; n = 133), and patients with a HxBCa (351.1+/-49.1; n = 69) (p <0.001). The urinary HAase levels were elevated (3 to 7 fold) in G2/G3 bladder cancer patients (26.2+/-3.2) as compared with normals (4.5+/-0.9) and patients with either GU conditions (5.8+/-1.3), HxBCa (8.2+/-2.6) or G1 tumors (9.7+/-2.5) (p <0.001). The HA test showed 83.1% sensitivity, 90.1% specificity and 86.5% accuracy in detecting bladder cancer, regardless of the tumor grade. The HAase test showed 81.5% sensitivity, 83.8% specificity and 82.9% accuracy to detect G2/G3 patients. Combining the inferences of the HA and HAase tests (HA-HAase test) resulted in detection of bladder cancer, regardless of tumor grade and stage, with higher sensitivity (91.2%) and accuracy (88.3%), and comparable specificity (84.4%). CONCLUSION: Our results show that the HA-HAase urine test is a noninvasive, highly sensitive and specific method for detecting bladder cancer and evaluating its grade.

Exploratory analysis on the effect of race on clinical outcome in patients with advanced prostate cancer receiving bicalutamide or flutamide, each in combination with LHRH analogues. The Casodex Combination Study Group.

BACKGROUND: Black race has been associated with a significantly increased risk of prostate cancer mortality. This exploratory analysis investigated the effect of race on the clinical outcome of combined androgen blockade (CAB). METHODS: Data for analysis were obtained from a double-blind, randomized, multicenter trial comparing CAB in the form of bicalutamide (50 mg once daily) or flutamide (250 mg three times daily) plus luteinizing hormone-releasing hormone analogs (LHRHa; goserelin acetate 3.6 mg, or leuprolide acetate 7.5 mg) in 813 patients with stage D(2) prostate cancer (median follow-up, 160 weeks). Patients were analyzed according to race (African American [AA], white, or other). The primary clinical events were disease progression and survival. RESULTS: Four hundred and four patients received bicalutamide/LHRHa and 409 received flutamide/LHRHa. Although treatment with bicalutamide/LHRHa resulted in slightly longer time to progression and survival time in white and AA males than treatment with flutamide/LHRHa, the differences between the treatment groups were not statistically significant. CONCLUSIONS: No marked effect of race on clinical outcome was observed regardless of antiandrogen, suggesting that similar treatment benefits are to be expected in either race.

Inhibition of prostate cancer metastasis in vivo: a comparison of 1,23-dihydroxyvitamin D (calcitriol) and EB1089.

The steroid hormone 1,25-dihydroxyvitamin D [1,25(OH)2D, also known as calcitriol] is known to inhibit the proliferation and to promote the differentiation of human prostate cancer cells. Additionally, we showed that 1,25(OH)2D markedly inhibits the invasiveness of human prostate cancer cells in vitro (G. G. Schwartz et al., Cancer Epidemiol. Biomark. Prev., 6: 727-732, 1997). These properties support the use of 1,25(OH)2D as differentiation therapy in prostate cancer. However, the use of 1,25(OH)2D in vivo is limited by the risk of hypercalcemia. We therefore compared the effects of 1,25(OH)2D and of EB1089, an analogue of 1,25(OH)2D with reduced calcemic effects, in an in vivo model of androgen-insensitive metastatic prostate cancer, the rat Dunning MAT LyLu prostate cancer model. Tumor growth and metastasis were studied using Copenhagen rats given s.c. injections of MAT LyLu cells. Fifty male rats were divided into five groups of 10 rats each. Four experimental groups received i.p. injections of low and high doses of 1,25(OH)2D and EB1089 (0.5 and 1.0 microg/kg, low and high, respectively). A control group received injections of vehicle only. Tumor volumes were measured three times per week. Rats were weighed weekly. The number of metastases to the lungs and the extent of hypercalcemia were evaluated. Compared with controls, tumor volumes were significantly smaller in all experimental groups. Similarly, the number of lung metastases (number of foci/lung) was reduced markedly by both 1,25(OH)2D and EB1089. Control rats developed 22.7 (+/- 1.98 SE) tumor foci per lung. Rats treated with 1,25(OH)2D and with EB1089 (1.0 microg/kg) developed 10.4 (+/- 2.81) and 7.70 (+/- 1.29) tumor foci, respectively (P < 0.001 and P < 0.0001, respectively; drug versus control). Compared with controls (10.79 +/- 0.1 mg/dl), serum calcium levels were significantly elevated in both 1,25(OH)2D and EB1089-treated rats (P < 0.01). However, EB1089 was significantly less calcemic than 1,25(OH)2D (12.59 +/- 0.21 mg/dl versus 14.47 +/- 0.46 mg/dl; 1.0 microg/kg; P < 0.001). Rats treated with 1,25(OH)2D showed marked weight loss: 20.0 +/- 1.9% and 26.3 +/- 1.7% of their initial weight (low and high doses, respectively, P < 0.001). Weight loss was significantly lower in rats treated with EB1089 at the high dose 8.4 (+/- 2.9) %. Moreover, rats treated with low-dose EB1089 gained 5.2 (+/- 3.7) % of their initial weight. In conclusion, 1,25(OH)2D and EB1089 showed marked and equivalent inhibition of prostate cancer metastasis in vivo. EB1089 was significantly less calcemic than 1,25(OH)2D and did not induce severe weight loss. This is the first report of a vitamin D analogue that significantly inhibits prostate cancer metastasis in vivo and that does so without producing cachexia or unacceptable hypercalcemia.

Secretion of bladder tumor-derived hyaluronidase activity by invasive bladder tumor cells.

Hyaluronic acid (HA), a glycosaminoglycan, promotes tumor metastasis and its small fragments are angiogenic. These small fragments are generated by degradation of HA by hyaluronidase (HAase). We measured urinary HAase levels of 196 individuals using an ELISA-like assay. The urinary HAase levels (31.1 +/- 3.7 mU/mg) of intermediate (G2) to high-grade (G3) bladder cancer patients are five- to seven-fold elevated as compared to those of normal individuals and patients with other genitourinary conditions or low-grade (G1) bladder cancer. The increase in urinary HAase levels is due to the secretion of a tumor-derived HAase which is elevated eight-fold in G2/G3 tumor tissues. The HAase in bladder tumor tissues is secreted by tumor epithelial cells and is associated with the invasive/metastatic potential of the tumor cells.

A new self-expanding lined stent-graft in the dog ureter: radiological, gross, histopathological and scanning electron microscopic findings.

Recurrent or intractable ureteral strictures pose a significant problem for the practicing urologist. Metallic stents have been used sparingly for this problem with varying success. We investigated the use of a stent-graft consisting of a metal stent lined with a porous biocompatible polymer to determine if the liner would prevent urothelial ingrowth. One ureter of each of 11 dogs was treated with either a metallic woven stent or stent-graft inserted retrograde via a midline cystotomy. Six bare wire stents (controls) and five lined with a new, porous, biocompatible, polycarbonate elastomer liner (Corethane) were placed. The animals were followed radiographically with intravenous urography (IVP) at 6 weeks and just prior to sacrifice (12 to 22 weeks). Gross, histological, and electron microscopic analyses were performed. The results demonstrate that all of the bare metal stented animals developed moderate to severe hydroureteronephrosis with significant urothelial hyperplasia and ingrowth through the spaces between the metal wires. The animals implanted with lined stents showed one instance of mild hydroureteronephrosis (observed radiographically but not grossly at time of sacrifice) and virtually no papillary in-growths of urothelium through the stent interstices. This obstructive phenomenon was prevented by the porous polymer lining. There was no evidence of biodegradation of the liner on scanning electron microscopy. Based upon these findings, the marriage of a biocompatible polymer which provokes minimal tissue reaction, and metallic stents which provide tremendous strength, seems to offer significant advantages when placed into the urinary tract to maintain ureteral luminal patency.

Comparison of goserelin and leuprolide in combined androgen blockade therapy.

OBJECTIVES: To perform exploratory analyses of data from a controlled trial that assessed the efficacy and tolerability of two antiandrogens, bicalutamide and flutamide, each combined with monthly depot preparations of leuprolide or goserelin, in patients with Stage D2 prostate cancer. One analysis compared goserelin plus antiandrogen therapy with leuprolide plus antiandrogen therapy; a second analysis compared the four combined androgen blockade (CAB) regimens. METHODS: This was a randomized, multicenter trial, open-label for luteinizing hormone releasing hormone analogue (LHRH-A) therapy, double-blind for antiandrogen therapy, with a two-by-two factorial design. Eight-hundred thirteen patients were allocated in a ratio of 2:1 to goserelin therapy (3.6 mg every 28 days) or leuprolide therapy (7.5 mg every 28 days) and 1:1 to bicalutamide therapy (50 mg once a day) or flutamide therapy (250 mg three times a day). The end points of time to progression and survival were assessed with a median of 160 weeks of follow-up. RESULTS: The percentages of progression events (70.9% versus 73.3%) and deaths (54.3% versus 56.8%) were similar for goserelin plus antiandrogen and leuprolide plus antiandrogen therapies. The hazard ratios for goserelin plus antiandrogen therapy to leuprolide plus antiandrogen therapy were 0.99 (95% confidence interval [CI] 0.84 to 1.18; P = 0.92) and 0.91 (95% CI 0.75 to 1.11; P = 0.34) for time to progression and survival, respectively. Goserelin plus antiandrogen and leuprolide plus antiandrogen therapies were generally well tolerated, and the side effects associated with depot administration occurred with a low frequency in the two groups. There were no significant differences among the goserelin plus bicalutamide, goserelin plus flutamide, or leuprolide plus bicalutamide therapy groups, but leuprolide plus flutamide therapy had a significantly poorer outcome than the other three therapies. The side-effect profiles for the four CAB groups were generally similar; diarrhea was more common among patients treated with flutamide and hematuria was more common among patients treated with bicalutamide. CONCLUSIONS: Although the results of these exploratory analyses should be interpreted with caution, they indicate that goserelin plus antiandrogen and leuprolide plus antiandrogen therapies are similarly well tolerated and have equivalent time to progression and survival, and that leuprolide plus flutamide therapy appears to be the least effective of the four CAB regimens.

Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Casodex Combination Study Group.

OBJECTIVES: To compare the efficacy and tolerability of bicalutamide and flutamide, each combined with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy, in patients with metastatic (Stage D2) prostate cancer. METHODS: This was a randomized, double-blind (for antiandrogen therapy), multicenter study with a two-by-two factorial design. Eight hundred thirteen patients were allocated 1:1 to bicalutamide (50 mg once daily) and flutamide (250 mg three times daily) and 2:1 to goserelin acetate (3.6 mg every 28 days) and leuprolide acetate (7.5 mg every 28 days). RESULTS: The median times to progression and death were 97 and 180 weeks for the bicalutamide plus LHRH-A group compared with 77 and 148 weeks for the flutamide plus LHRH-A group. The hazard ratio for time to progression for bicalutamide plus LHRH-A to flutamide plus LHRH-A was 0.93 (95% confidence interval [CI] 0.79 to 1.10, P = 0.41) and that for survival time was 0.87 (95% CI 0.72 to 1.05, P = 0.15). The therapies were generally well tolerated. The most common adverse event in the two groups was hot flashes. The incidence of hematuria was significantly higher for the bicalutamide plus LHRH-A group than for the flutamide plus LHRH-A group (12% versus 6%, P = 0.007), but no patient withdrew from therapy because of hematuria. There was a significantly (26% versus 12%, P < 0.001) higher incidence of diarrhea and more withdrawals for diarrhea (25 patients versus 2) for the flutamide plus LHRH-A group relative to the bicalutamide plus LHRH-A group. CONCLUSIONS: With a median follow-up time of 160 weeks, the combination of bicalutamide plus LHRH-A was well tolerated and had equivalent time to progression and survival compared with flutamide plus LHRH-A. Treatment with bicalutamide plus LHRH-A resulted in longer median survival than treatment with flutamide plus LHRH-A.

Tumor-associated hyaluronic acid: a new sensitive and specific urine marker for bladder cancer.

Hyaluronic acid (HA), a glycosaminoglycan, is known to promote tumor cell adhesion and migration, and its small fragments stimulate angiogenesis. We compared levels of HA in the urine of normal individuals and patients with bladder cancer or other genitourinary conditions, using a sensitive ELISA-like assay. Among the 144 specimens analyzed, the urinary HA levels of bladder cancer patients with G1 (255 +/- 41.7 ng/mg), G2 (291.8 +/- 68.3 ng/mg) and G3 (428.4 +/- 67 ng/mg) tumors are 4-9-fold elevated as compared to those of normal individuals (44.7 +/- 6.2 ng/mg) and patients with other genitourinary conditions (69.5 +/- 6.8 ng/mg; P < 0.001). Urinary HA measurement by the ELISA-like assay shows a sensitivity of 91.9% and specificity of 92.8% to detect bladder cancer. Thus, urinary HA measurement is a simple, noninvasive yet highly sensitive and specific method for bladder cancer detection. The increase in urinary HA concentration is a direct correlate of the elevated tumor-associated HA levels, because the HA levels are also elevated (3-5-fold) in bladder tumor tissues (P < 0.001). The profiles of urinary HA species of normal individuals and bladder cancer patients are different. Although only the intermediate-size HA species are found in the urine of normal and low-grade bladder tumor patients, the urine of high-grade bladder cancer patients contains both the high molecular mass and the small angiogenic HA fragments. These urinary HA fragments stimulate a mitogenic response (2.4-fold) in primary human microvessel endothelial cells, suggesting that the small HA fragments may regulate tumor angiogenesis by modulating endothelial cell functions.

Tumor-derived hyaluronidase: a diagnostic urine marker for high-grade bladder cancer.

The detection of high-grade bladder tumors prior to invasion is crucial for a good prognosis. We recently found that the levels of hyaluronic acid (HA), a glycosaminoglycan, are elevated in the urine of bladder cancer patients, and small angiogenic HA fragments are present in the urine of high-grade bladder cancer patients. Hyaluronidase is an enzyme that degrades HA into small angiogenic fragments. We compared the urinary hyaluronidase levels of normal individuals and patients with bladder cancer or other genitourinary conditions, using a substrate (HA)-gel technique and an ELISA-like assay. Among the 139 specimens analyzed, the urinary hyaluronidase levels in patients with G2/G3 tumors (33.4 +/- 4.5 milliunits/mg protein) are 5-8-fold higher than those in normal individuals (4.2 +/- 1.2 milliunits/mg protein) and those in patients with G1 tumors (6.5 +/- 1.7 milliunits/mg protein) or other genitourinary conditions (7.4 +/- 1.4 milliunits/mg protein; P < 0.001). Urinary hyaluronidase measurement shows a sensitivity of 100% and a specificity of 88.8% to detect high-grade bladder (G2/G3) tumors. Thus urinary hyaluronidase measurement is a simple, noninvasive yet highly specific and sensitive method for high-grade bladder cancer detection. The increase in urinary hyaluronidase levels is due to the secretion of a tumor-associated hyaluronidase into the urine because the hyaluronidase levels in G2/G3 tumor tissues are also higher (6-7-fold) than those in normal bladder and G1 tumor tissues (P < 0.001). The bladder tumor-associated hyaluronidase activity is distinct from other hyaluronidases, has a pH optimum of 4.3, and is attributed to two proteins with molecular masses of 65 kD (p65) and 55 kD (p55).

A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma. Analysis of time to progression. CASODEX Combination Study Group.

BACKGROUND: A randomized, multicenter trial, double-blind for antiandrogen therapy, compared the antiandrogens bicalutamide and flutamide, each combined with luteinizing hormone-releasing hormone analogue therapy (LHRH-A) in 813 patients with Stage D2 prostate carcinoma. An analysis of time to progression (median follow-up, 95 weeks) was performed to augment previous analyses of time to treatment failure and time to death. METHODS: Patients were randomly assigned 1:1 to double-blind antiandrogen therapy, receiving either bicalutamide (50 mg once daily) or flutamide (250 mg three times daily), and were assigned 2:1 to LHRH-A with goserelin acetate (3.6 mg every 28 days) or leuprolide acetate (7.5 mg every 28 days). The primary endpoint of the trial was time to treatment failure, defined as an adverse event leading to withdrawal of randomized therapy, objective progression, death, or withdrawal from study therapy for any reason. Secondary endpoints were time to death, quality of life, and subjective response. The current analysis of time to progression included progression data collected prospectively for 561 patients (69%) and retrospectively for 252 patients (31%). RESULTS: Disease progression occurred for 223 of 404 patients (55%) in the bicalutamide plus LHRH-A group and for 235 of 409 patients (58%) in the flutamide plus LHRH-A group. The hazard ratio for time to progression of bicalutamide plus LHRH-A to that of flutamide plus LHRH-A was 0.9 (two-sided 95% confidence interval [CI], 0.75 to 1.08; P = 0.26). The upper one-sided 95% CI was 1.05, which met the definition of equivalence (< 1.25). CONCLUSIONS: At a median follow-up time of 95 weeks, bicalutamide plus LHRH-A and flutamide plus LHRH-A had equivalent time to progression.

Enhancement of radiation response of prostatic carcinoma by lonidamine.

Potential application of lonidamine (LND) to enhance radiation toxicity in prostate cancer was investigated using human prostate cancer cell lines and a rat tumor model (Dunning MAT LyLu). LND alone was cytotoxic with 50% inhibition concentration (IC50) between 0.5 and 0.8 mM. Preincubation with LND increased clonogenic toxicity of radiation. The sensitizer enhancement ratio was 1.8 to 2.2, depending on the cell line tested and it was consistent with inhibition of repair from potentially lethal damage. LND had limited effect in vivo on the Dunning model, consistent with its in vitro effect on the same cell line. LND did not alter the primary growth of the tumor. Fractionated irradiation caused a 40% decrease in tumor growth. LND injection (50 mg/kg) before fractionation did not cause any further decrease in tumor growth. Radiation dose fractionation and the combination treatment significantly reduced tumor metastasis in lungs.

Radical prostatectomy: is complete resection of the seminal vesicles really necessary?

PURPOSE: We determined the frequency of prostate cancer extension into the distal 1 cm. of seminal vesicles, and reconsidered whether complete excision of the seminal vesicles during radical prostatectomy is always necessary. MATERIAL AND METHODS: After en bloc removal with the specimen in 71 consecutive radical prostatectomies, the distal 1 cm. of each seminal vesicle was transected and separately analyzed for tumor involvement. RESULTS: Mean patient age was 61.8 years (range 40 to 72). Preoperative prostate specific antigen (PSA) ranged from 0.8 to 37 ng./dl. (median 7.3), and 18 patients had a PSA of 10 or more. Clinical stages were T1b in 1 case T1c in 37, T2a in 12, T2b in 10, T2c in 6 and T3a in 1. Preoperative Gleason sums ranged from 4 to 8 (median 6) with 21 patients (30%) having a sum of 7 or more. Of 71 patients 12 (17%) and seminal vesicle invasion (5 bilaterally). In no case did tumor extend into the distal 1 cm. of the seminal vesicle. PSA at diagnosis ranged from 4.2 to 30 ng./dl., with 4 of 12 patients having a PSA of 10 or more. Preoperative clinical stages were T1c in 5 cases, T2a in 3, T2b in 2 and T2c in 2. Five of the 12 patients (42%) had positive surgical margins and 11 (92%) had a postoperative Gleason sum of 7 or more. CONCLUSIONS: In 71 consecutive patients undergoing radical prostatectomy no tumor was found in the distal 1 cm. of the seminal vesicles, including 12 with seminal vesicle invasion. We continue to advocate complete excision of the seminal vesicles during radical prostatectomy. However, if dissection is difficult and a small fragment is left behind, the prognosis is unlikely to be altered.

Modulation of aromatase activity by growth factors in an androgen sensitive human prostate cancer cell line, LNCaP.

The effects of steroids and peptide growth factors on aromatase activity in an androgen sensitive human prostate cancer cell line (LNCaP) were investigated. Factors were selected based on their observed modulation of the enzyme in other tissues. Incubation with epidermal growth factor and transforming growth factor-I decreased aromatase activity in LNCaP cells by 25-40%. Insulin like growth factor-1, dexamethasone, dibutyryl cAMP and phorbol 12-myristate 13-acetate, all of which are modulators of aromatase in other tissues, had no significant effect on aromatase activity in LNCaP cells. In addition, the cAMP-dependent protein kinase and protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2 methylpiperazine (H-7) had no effect on the enzyme activity. Factors affecting prostatic aromatase may be distinct from those for other known species.