PM01183, a new DNA minor groove covalent binder with potent in vitro and in vivo anti-tumour activity.

BACKGROUND AND PURPOSE: PM01183 is a new synthetic tetrahydroisoquinoline alkaloid that is currently in phase I clinical development for the treatment of solid tumours. In this study we have characterized the interactions of PM01183 with selected DNA molecules of defined sequence and its in vitro and in vivo cytotoxicity. EXPERIMENTAL APPROACH: DNA binding characteristics of PM01183 were studied using electrophoretic mobility shift assays, fluorescence-based melting kinetic experiments and computational modelling methods. Its mechanism of action was investigated using flow cytometry, Western blot analysis and fluorescent microscopy. In vitro anti-tumour activity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the in vivo activity utilized several human cancer models. KEY RESULTS: Electrophoretic mobility shift assays demonstrated that PM01183 bound to DNA. Fluorescence-based thermal denaturation experiments showed that the most favourable DNA triplets providing a central guanine for covalent adduct formation are AGC, CGG, AGG and TGG. These binding preferences could be rationalized using molecular modelling. PM01183-DNA adducts in living cells give rise to double-strand breaks, triggering S-phase accumulation and apoptosis. The potent cytotoxic activity of PM01183 was ascertained in a 23-cell line panel with a mean GI(50) value of 2.7 nM. In four murine xenograft models of human cancer, PM01183 inhibited tumour growth significantly with no weight loss of treated animals. CONCLUSIONS AND IMPLICATIONS: PM01183 is shown to bind to selected DNA sequences and promoted apoptosis by inducing double-strand breaks at nanomolar concentrations. The potent anti-tumour activity of PM01183 in several murine models of human cancer supports its development as a novel anti-neoplastic agent.

[Melanosis of the bladder: a very uncommon entity]. / Melanosis vesical: una entidad de muy infrecuente presentación.

Melanosis of the bladder is a rare entity characterized by anomalous deposits of melanin-containing pigment on the vesical urothelium without melanocytic atypia or associated malignant melanoma. To our knowledge and following such strict criteria, there are only five cases previously reported. The biological potential of this entity is uncertain because of the rarity of their. We report one case of simple melanosis of the bladder confirmed by histological examination and inmunohistochemistry analysis. We believe that recognition of this entity is important.

Melanosis vesical: una entidad de muy infrecuente presentación / Melanosis of the bladder: a very uncommon entity

La melanosis vesical es una entidad caracterizada por depósito anómalo de pigmento melánico en la mucosa urotelial sin atipia celular asociada, que condiciona una coloración oscura de la mucosa vesical en su visión macroscópica. Es muy infrecuente, ya que, en nuestra revisión de la literatura únicamente encontramos cinco casos publicados. El potencial biológico de esta entidad es desconocido, debido a la extremada rareza en su presentación. Presentamos un caso de melanosis vesical confirmado por estudio histológico y análisis inmunohistoquímico. Pensamos que es necesario tener presente la existencia de esta entidad, así como saber reconocerla para poder establecer el diagnóstico diferencial con el melanoma vesical maligno

Melanosis of the bladder is a rare entity characterized by anomalous deposits of melanin-containing pigment on the vesical urothelium without melanocytic atypia or associated malignant melanoma. To our knowledge and following such strict criteria, there are only five cases previously reported. The biological potential of this entity is uncertain because of the rarity of their. We report one case of simple melanosis of the bladder confirmed by histological examination and inmunohistochemistry analysis. We believe that recognition of this entity is important

[Post-transplantation renal rupture]. / Rotura renal postransplante.

INTRODUCTION: Renal allograft rupture in the transplanted patient represents a usually early postoperatory complication threatening graft and patient survival. Urgent management is often required. MATERIAL AND METHODS: Renal transplanted patients which had rupture of the renal allograft have been reviewed retrospectively. Between February 1980 and June 1996 a total of 868 renal transplants were performed, and 21 (2.41%) suffered from allograft rupture. Diagnosis was based mainly on the symptoms, blood analysis to test hematocrit value, and ultrasounds. RESULTS: Men age of the patients was 34 years old (21-49), 15 (71.4%) males and 6 (28.6%) females. Evolution was as follow: 4 patients underwent extracapsular nephrectomy due to non-functioning kidney; in 16 patients the graft could be preserved using different methods of renal corsetage (lyophilized human dura was applied in 8 cases, fascia lata in one, fascia lata and lyophilized human dura in 3 cases, and polyglycolic acid mesh in other 4 patients); and finally one patient was managed conservatively. There was no intra and post-operatory mortality. Four patients died lately of other causes not related to renal transplantation. Other 4 patients underwent chronic rejection and fail of the renal function. Two of these four patients have already received their second graft. A total of 13 patients have a good renal function (61.9%). CONCLUSIONS: Early diagnosis of the renal allograft rupture must be the main objective in order to initiate as soon as possible therapeutic measures that firstly should be aimed to preserve the graft (medically or surgically). Nephrectomy must be reserved for renal allograft rupture secondary to venous thrombosis and other situations threatening life.

[Surgical wound infection in renal transplant recipients]. / Infección de herida operatoria en trasplantados renales.

Between 1980 and 1991, 504 transplantations were performed in our hospital. All patients received pre-surgical therapy with antibiotics. The total incidence of surgical wound infection was 15 cases (3%). After reviewing all parameters that could have been involved in the development of these infections, it become apparent that diabetes mellitus, more than one transplant in the same patient, development of haematoma in the wound and presence of urinary fistulae were statistically significant (p < 0.05). On the other hand, the use of the different immunosuppressive regimes (azathioprin and cyclosporin) and acute tubular necrosis showed no statistical significance (p > 0.05); also, no relationship was found between infection and acute graft rejection.

[Duplex echography in acute scrotum. Diagnostic possibilities]. / El eco duplex en el escroto agudo. Posibilidades diagnósticas.

Acute scrotum is a frequent reason for consultation at the urological emergency service. The most common causes, apart from trauma, are acute orchiepididymitis, torsion of the hydatids of Morgagni and torsion of the spermatic cord. Apart from a detailed examination of patient history and a careful physical examination, few diagnostic techniques can be utilized. To date, only the Doppler ultrasound has proved useful in corroborating the suspicion of vascular involvement, although this technique is very limited. With the availability of the duplex ultrasound, the possibility of making the differential diagnosis in the acute scrotum is enhanced. This technique permits morphological and functional assessment and avoids unnecessary exploration surgery within the scrotum.

[Valves of the anterior urethra]. / Valvas de uretra anterior.

Despite the cases reported in the literature, anterior urethral valves continue to be an uncommon condition. The foregoing has to be considered when evaluating children with urinary obstruction or recurrent infections. A case of anterior urethral valves associated with segmental saccular dilatation of the urethra is described and the diagnostic methods are highlighted.

[Horseshoe kidney: its usefulness in transplantation]. / Riñón en herradura: su utilidad en el trasplante.

The horseshoe kidney is useful as a graft and should be transplanted. The technical difficulties can be avoided by en bloc removal, perfusion in situ with Collins solution, and bench surgery during graft preparation.

[Use of the great epiploon in the treatment of idiopathic retroperitoneal fibrosis]. / Empleo del epiplón mayor en el tratamiento de la fibrosis retroperitoneal idiopática.

Immediately after ureterolysis in the treatment of idiopathic retroperitoneal fibrosis, we covered the ureter with a large epiploon, forming a sheath with omentum covering the entire ureter from the renal pelvis to the juxtavesical area of the same. This technique revitalizes the ischemic ureter resulting from ureterolysis and protects against the reinclusion of the ureter mobilized inside the sclerolipomatous mass.

[Perineal ectopic testis]. / Testiculo ectopico perineal.

The authors present three cases of perineal, testicle ectopia, two of which were diagnosed and treated in the Urology Department of the "La Fe" Hospital. The other observation was diagnosed and treated by one of us privately. The treatment was surgical in all the cases and good results were obtained in them all. They discuss the etiopathogeny, clinical characteristics and the uselessness of hormone treatment.

[Torsion of the hydatid of Morgagni]. / Torsión de las hidatides de Morgagni.

The authors present 6 cases of torsion of Morgagni's hydatid treated in the Emergency Urology Department over a two-year period. They stress the importance of the clinical diagnosis, as well as the differential diagnosis with other "acute, testicular bag" processes, in particular with funicular torsion. Surgical treatment is the only way of overcoming the pain, confirming the diagnosis and preventing the risk of secondary, testicular atrophy.