Andreas Jungwirth

Inhibition of growth of androgen-independent DU-145 prostate cancer in vivo by luteinising hormone-releasing hormone antagonist cetrorelix and bombesin antagonists RC-3940-II and RC-3950-II

The aim of this study was to test the antagonist of LH-RH (Cetrorelix), agonist [D-Trp6]LH-RH (triptorelin) and new bombesin antagonists RC-3940-II and RC-3950-II for their effect on the growth of an androgen-independent prostate cancer cell line, DU-145, xenografted into nude mice. Xenografts were grown in male nude mice, and after 4 weeks, the animals were treated either with saline (control) or with one of the analogues. One group of mice was given a combination of Cetrorelix and RC-3950-II. Treatment was given for 4 weeks. Tumour and body weights, and tumour volumes were measured. At sacrifice, tumours were dissected for histological examination and receptor studies. Serum was collected for measurement of hormone levels. The final tumour volume in control animals injected with saline was 577 +/- 155 mm3 and that of animals treated with Cetrorelix only 121.4 +/- 45 mm3 (P < 0.01). Bombesin antagonists RC-3940-II and RC-3950-II also significantly reduced DU-145 tumour volume in nude mice to 84.9 +/- 19.9 and 96.8 +/- 28 mm3, respectively. Agonist [D-Trp6]LH-RH did not significantly inhibit tumour growth. Serum levels of LH were decreased to 0.08 +/- 0.02 ng/ml (P < 0.05) in the Cetrorelix treated group as compared to 1.02 +/- 0.1 ng/ml for the controls, and testosterone levels were reduced to castration levels (0.01 +/- 0.01 ng/ml). Specific receptors for EGF and LH-RH in DU-145 tumours were significantly downregulated after treatment with Cetrorelix, RC-3940-II and RC-3950-II. Although LH-RH could be a local regulator of growth of prostate cancer, the fall in LH-RH receptors is not fully understood and the inhibitory effects of Cetrorelix and bombesin antagonists on DU-145 tumour growth might be attributed at least in part to a downregulation of EHF receptors. Since Cetrorelix and bombesin antagonists inhibit growth of androgen-independent DU-145 prostate cancers, these compounds could be considered for the therapy of advanced prostate cancer in men, especially after relapse.

Inhibition of in vivo proliferation of androgen-independent prostate cancers by an antagonist of growth hormone-releasing hormone.

Tumour-inhibitory effects of a new antagonist of growth hormone-releasing hormone (GH-RH), MZ-4-71, were evaluated in nude mice bearing androgen-independent human prostate cancer cell lines DU-145 and PC-3 and in Copenhagen rats implanted with Dunning R-3327 AT-1 prostatic adenocarcinoma. After 6 weeks of therapy, the tumour volume in nude mice with DU-145 prostate cancers treated with 40 microg day(-1) MZ-4-71 was significantly decreased to 37 +/- 13 mm3 (P < 0.01) compared with controls that measured 194 +/- 35 mm3. A similar inhibition of tumour growth was obtained in nude mice bearing PC-3 cancers, in which the treatment with MZ-4-71 for 4 weeks diminished the tumour volume to 119 +/- 35 mm3 compared with 397 +/- 115 mm3 for control animals. Therapy with MZ-4-71 also significantly decreased weights of PC-3 and DU-145 tumours and increased tumour doubling time. Serum levels of GH and IGF-I were significantly decreased in animals treated with GH-RH antagonist. In PC-3 tumour tissue, the levels of IGF-I and IGF-II were reduced to non-detectable values after therapy with MZ-4-71. The growth of Dunning R-3327 AT-1 tumours in rats was also significantly inhibited after 3 weeks of treatment with 100 microg of MZ-4-71 day(-1) i.p. as shown by a reduction in tumour volume and weight (both P-values < 0.05). Specific high-affinity binding sites for IGF-I were found on the membranes of DU-145, PC-3 and Dunning R-3327 AT-1 tumours. Our results indicate that GH-RH antagonist MZ-4-71 suppresses growth of PC-3, DU-145 and Dunning AT-1 androgen-independent prostate cancers, through diminution of GH release and the resulting decrease in the secretion of hepatic IGF-I, or through mechanisms involving a lowering of tumour IGF-I levels and possibly an inhibition of tumour IGF-I and IGF-II production. GH-RH antagonists could be considered for further development for the therapy of prostate cancer, especially after the relapse.

Luteinizing hormone‐releasing hormone antagonist Cetrorelix (SB‐75) and bombesin antagonist RC‐3940‐II inhibit the growth of androgen‐independent PC‐3 prostate cancer in nude mice

Hormones like bombesin (BN)/gastrin‐releasing peptide (GRP) and luteinizing hormone‐releasing hormone (LH‐RH) and growth factors such as epidermal growth factor (EGF) might be involved in the relapse of prostate cancer under androgen ablation therapy. Interference with receptors for BN/GRP, LH‐RH, or EGF might provide a therapeutic approach to inhibit tumor growth of androgen‐independent prostate cancer.

Evaluation of transition zone and lateral sextant biopsies for prostate cancer detection after initial sextant biopsy

OBJECTIVES To assess the value of transition zone and lateral sextant biopsies for the detection of prostate cancer after a previous sextant biopsy was negative. METHODS A total of 74 prostates after radical prostatectomy were used to perform biopsies ex vivo. First, a sextant biopsy was taken, then two different rebiopsy techniques were performed. Rebiopsy technique A consisted of a laterally placed sextant biopsy and two cores per side of the transition zones only. Rebiopsy technique B included a standard sextant biopsy and two cores per side from the lateral areas of the prostate. The biopsies were taken using ultrasound guidance to sample the areas of interest precisely. RESULTS The initial sextant biopsy found 39 prostate cancers. Rebiopsy technique A found 12 cancers (34%). In this group, a laterally placed sextant biopsy found 12 cancers; transition zone biopsies revealed cancer in 5 cases, but no additional tumor was found. Rebiopsy technique B detected 23 prostate cancers (66%). Fourteen tumors were found after a second standard sextant biopsy, and nine additional tumors were found in the lateral areas. CONCLUSIONS Sextant biopsy has a low sensitivity of only 53%. A biopsy including the transition zones is not the ideal technique for detecting the remaining tumors. Therefore, transition zone biopsies should be reserved for patients with multiple previous negative biopsies of the peripheral zone. A subsequent sextant biopsy with additional cores from the lateral areas of the prostate is favorable if rebiopsy is necessary after a negative sextant biopsy.

Effective long-term androgen suppression in men with prostate cancer using a hydrogel implant with the GnRH agonist histrelin ☆

OBJECTIVES To evaluate the effectiveness of a hydrogel implant containing the gonadotropin-releasing hormone (GnRH) agonist histrelin in suppressing testosterone production in men with prostate cancer and to determine the effective dose (one, two, or four implants). METHODS Forty-two men with prostate cancer and indications for androgen ablation were treated with one, two, or four implants. In two of the clinics, comprising 27 subjects, the treatment period was 12 months, with replacement with the same number of implants at 12-month intervals. In a third clinic, which treated 15 subjects, the implants were left in place for up to 30 months. The total experience was 605 treatment months. RESULTS The histrelin levels were detected in serum proportional to the number of implants placed. The response, however, was similar among all three dose levels, with testosterone and luteinizing hormone essentially completely suppressed. Serum testosterone levels decreased from 21.9 +/- 17.6 nmol/L to 0.93 +/- 1.57 nmol/L within 1 month and were maintained at 0.55 +/- 0.24 nmol/L at 6 months and 0.60 +/- 0.28 nmol/L after 12 months of treatment. Of the 38 assessable patients, 35 (92%) had castrate levels of testosterone within 4 weeks of the initial implant placement. All patients followed for up for 12 months after placement of the initial set of implants maintained suppression of testosterone production while the implant was in place. CONCLUSIONS The histrelin hydrogel implant provided adequate and reliable delivery of the potent GnRH agonist histrelin during at least 1 year using a single implant in men with prostate cancer. No apparent advantages were found in using more than one implant, and the question of the possible effectiveness of even lower doses remains open. This treatment modality appears to be both safe and effective.

Effect of active immunization against luteinizing hormone-releasing hormone on the androgen-sensitive Dunning R3327-PAP and androgen-independent Dunning R3327-AT2.1 prostate cancer sublines.

The objective of this study was to determine the effect of active immunization against LHRH on the growth characteristics and histology of subcutaneously implanted tumors of the androgen‐sensitive Dunning R3327‐PAP and androgen‐independent R3327‐AT2.1 rat prostate adenocarcinoma sublines.

Androgens and the prostate

The prostate is androgen-dependent, requiring testosterone for its growth, development, differentiation and function. The involution of the prostate gland is initiated by testosterone depriviation (orchidectomy, medical castration). Subsequent administration of exogenous androgen and/or cessation of medical androgen blockade, however, results in re-growth of the prostate gland. However, it only attains its original size, and the response to androgen does not cause prostatic overgrowth.

Effect of chronic administration of a new potent agonist of GH-RH(1-29)NH2 on linear growth and GH responsiveness in rats.

The effects of a repeated or continuous administration of a potent agonistic analog of growth hormone-releasing hormone (GH-RH), [Dat1, Thr8, Orn12,21, Abu15, Nle27, Asp28, Agm29] hGH-RH(1-29)(JI-36), on the linear growth and the GH responses to bolus injections of GH-RH(1-29)NH2 were investigated in male rats about 7 weeks old. Body weight and tail length were monitored. Basal serum GH and IGF-I concentrations and GH responses to GH-RH(1-29)NH2 were measured by RIA. Chronic administration of GH-RH agonist JI-36 by continuous release from osmotic minipumps at the rate of 0.2 microgram/h or twice daily injections of 0.5 and 5 micrograms/rat for 4 weeks significantly speeded up the growth of rats as measured by the tail length. The acceleration of growth was similar in the 3 groups and was associated with stimulation of IGF-I secretion. The GH response to bolus injection of GH-RH(1-29)NH2 was preserved in all groups and no attentuation of the response occurred in rats treated for 4 weeks with agonist JI-36 as compared with the control group. Our results indicate that chronic administration of GH-RH agonist JI-36 significantly increases the growth rate without affecting somatotroph responsiveness in rats. It is therefore likely that this class of GH-RH agonists may be useful clinically.

Erektile Dysfunktion@@@Erectile dysfunction

SummaryErectile Dysfunction is one of the most prevalent sexual disorders in men. According to the current literature the prevalence is about 16% for all men. The diagnostic workup of a patient suffering from E.D. is a detailed anamnesis, a physical and endocrinological evaluation and the suggestion of the optimal therapeutic treatment. The therapeutic application of PDE-5 inhibitors has made the therapy of E.D. much easier. It is a safe and highly efficient therapeutic option. But man must not forget that in severe cases of erectile dysfunction, the application of SKAT therapy, penile implants or vacuum devices might be necessary. Since a functioning sex life is important not only for the men, but also for the couple, a more open attitude of us, physicians, is desirable to help more men who suffer from this sexual dysfunction.ZusammenfassungDie erektile Dysfunktion ist eine der häufigsten Sexualstörungen bei Männern. Die Prävalenz beträgt lt. aktueller Literatur ca. 16 % . Die diagnostische Abklärung eines E. D.-Patienten umfasst eine detaillierte Anamnese, eine physikalische Untersuchung und eine endokrinologische Basisevaluation. Die therapeutische Verabreichung von PDE-5-Inhibitoren hat die Therapie der E. D. um vieles einfacher gemacht, da es sich um eine sichere und hoch effiziente orale Therapieoption handelt. Aber man darf nicht vergessen, dass in schweren Fällen fiese Therapie teilweise nicht ausreichend hilft und die Verabreichung der SKAT-Therapie und die Implantation von Penisprothesen oder die Verwendung von Vakuumpumpen notwendig sein kann. Da ein funktionierendes Sexualleben nicht nur für den betroffenen Mann allein, sondern immer auch für das Paar wichtig ist, wäre ein offener Zugang zu diesem Thema durch uns Ärzte wünschenswert, um mehr Männern mit dieser Sexualstörung helfen zu können.