Takashi Kubo

Two Circulatory Routes Within the Human Corpus Cavernosum Penis: A Scanning Electron Microscopic Study of Corrosion Casts

The microvascular architecture of the human corpus cavernosum penis was studied by scanning electron microscopy of vascular corrosion casts. The corpus cavernosum was supplied by the penile deep artery. It gave off branches to become either arteries distributed within the corpus cavernosum or those directly supplying the corpus spongiosum urethrae. The former arteries further divided into small arteries which fell into two categories: 1) arteries breaking up into capillaries, and 2) arteries draining directly into the cavernous sinuses. The capillaries were collected into venular networks just beneath the tunica albuginea (the subalbugineal venular plexus), while the cavernous sinuses were collected into venules at the periphery of the corpus cavernosum. These postcavernous venules also received venules from the subalbugineal venular plexus, and left the corpus cavernosum. Thus, two circulatory routes are evident within the corpus cavernosum. These findings suggested that the penile erectile cycle is controlled by hemodynamic changes between these two routes within the corpus cavernosum.

Antitumor Effects of Angiogenesis Inhibitor O-(Chloroacetyl-Carbamoyl) Fumagillol (TNP-470) against Murine Renal Cell Carcinoma

PURPOSE The effect of 0-(chloroacetyl-carbamoyl) fumagillol (TNP-470) on tumor growth and metastasis is investigated. MATERIALS AND METHODS BALB/c mice were inoculated with Renca murine tumor and graded doses of TNP-470 were given subcutaneously every other day beginning on day 1 and ending on day 9. Tumor angiogenesis was measured quantitatively by a colorimetric assay. RESULTS TNP-470 inhibited tumor growth and prolonged the life span of Renca-bearing mice in a dose-dependent manner. Body weight-loss was not observed in the mice given less than 30 mg./kg./day. When the treatment was delayed on day 6, TNP-470 did not inhibit tumor growth, pointing to the importance of the timing of drug administration in relation to disease stage. Tumor angiogenesis was inhibited 33 to 62% of the control level by TNP-470. Furthermore, TNP-470 reduced pulmonary and hepatic metastatic foci of intravenously inoculated Renca and of the tumor inoculated in the spleen. CONCLUSION These data suggest that TNP-470 may be effective as a treatment of renal cell carcinoma, especially when micrometastases are involved.

In Vitro Contraction of the Canine Corpus Cavernosum Penis by Direct Perfusion with Prolactin or Growth Hormone

PURPOSE It is well established that hyperprolactinemia, most typically seen in prolactinoma patients, causes hypogonadism and impotence. There seems to be a good possibility that hyperprolactinemia causes impotence, at least partially via some intrinsic property of prolactin (PRL), rather than through its suppressive effects on the hypothalamic-pituitary-gonadal testosterone dynamics. In the present investigation, we used an in vitro canine model to attempt to clarify whether direct action of PRL on the corpus cavernosum penis may lead to erectile insufficiency. Growth hormone (GH) and placental lactogen (PL), both having close structural and functional homologies to PRL, were also studied. MATERIALS AND METHODS Isometric tension measurement with cavernous strips was performed in the presence or absence of 10(-5) to 10(-9) M. PRL, GH, or PL in the perfusion medium. The tension change induced by the test substances was normalized relative to that induced by 120 mEq KCl. RESULTS Both PRL and GH produced dose-related elevations (p < 0.01) of the cavernous tension, whereas PL and thiol-cleaved PRL in comparable doses were without effect (p > 0.05). When the tension rise produced by 120 mEq KCl was taken as 100%, the maximum contractions produced by PRL and GH were 80% and 110%. The minimum effective concentration was 10(-8) to 10(-7) M. for both PRL and GH. Pretreatment with indomethacin (10(-5) M.), but not tetrodotoxin (10(-5) M., partially suppressed (p < 0.05) the effects of PRL. CONCLUSION These results suggest that PRL and GH directly and specifically produced contraction of the corpus cavernosum penis, resulting in erectile insufficiency, and that the effect of PRL is partially mediated by prostaglandin.

Suppression by Prolactin of the Electrically Induced Erectile Response through its Direct Effect on the Corpus Cavernosum Penis in the Dog

PURPOSE Men become impotent when exposed to hyperprolactinemia. To clarify its mechanisms the effects of intracorporal infusion of prolactin on electrically induced penile erection were evaluated in 12 male dogs. MATERIALS AND METHODS Prolactin (10 micrograms./ml.) or control saline was directly infused into the corpus cavernosum penis 5 minutes before electrical pulse stimulation of the pelvic nerve and the intracorporal pressure was monitored. RESULTS In 8 dogs erection was markedly suppressed or completely abolished by prolactin. In the remaining 4, this effect of prolactin became manifest only when the ipsilateral internal pudenal artery was ligated. Saline infusion was without effect. CONCLUSIONS An excess of prolactin directly inhibited the smooth muscle relaxation of corpus cavernosum penis.

Analysis of genetic alterations in renal cell carcinoma using the polymerase chain reaction.

Very frequent loss of heterozygosity (LOH) on chromosome 3p has been found in human renal cell carcinoma (RCC). In the present study, we examined LOH at the retinoblastoma (RB), mutated in colorectal cancer (MCC) and adenomatous polyposis coli (APC) tumour suppressor genes loci, and mutations of the H-, K-, and N-ras oncogenes. We performed these studies using the polymerase chain reaction (PCR) method followed by restriction fragment length polymorphism (RFLP) and single-strand conformation polymorphism (SSCP) analyses. LOH was detected in 2 of 11 (18.2%), and 2 of 14 (14.3%) informative cases at the MCC and APC loci, respectively, and in none of 15 informative cases at the RB locus in 25 RCCs. LOH at the MCC was accompanied by LOH at the APC locus in two RCCs. No mutation was detected in H-, K-, and N-ras genes in 39 RCCs. Thus, alterations of the known tumour suppressor genes and the ras oncogenes were infrequent events in RCC. The results suggest that the genetic pathway in the genesis of RCC differs considerably from that of other common human carcinomas.

Quantitative analysis of outflow pathway of corpora cavernosa by pressure flow technique.

Using a pressure flow technique, quantitative analysis of the physiological characteristics of the outflow pathway of the corpus cavernosum was carried out in 19 male dogs weighing 7.5 to 23.0 kg. Pressure flow curves were made on dogs whose pelvic nerve was stimulated electrically and on dogs left unstimulated. When a cyclical change in saline perfusion rate was applied without nerve stimulation, the variable of the intracorporeal pressure showed a large hysteretic loop, indicating that the resistance of the outflow canals to flow was altered by the distension of the sinusoidal space. In dogs whose pelvic nerve was stimulated, the pressure flow curves shifted to the left side in comparison with the outward phase of the pressure flow curve of animals without pelvic nerve stimulation, and this curve piled on the returning phase. No hysteretic relation was observed between the outward and returning phase of the pressure flow curve with pelvic nerve stimulation, but in the detailed analysis, in which the % flow rate was used instead of actual flow rate of saline perfusion, a small hysteretic loop based on the difference of the elasticity of the outlet canals was found. The distension of the corpora cavernosa and the pelvic nerve electrostimulation probably act as the triggers of the same occlusive mechanism in the outflow pathway. The percentage decrease in the blood flow in the outflow canal of the corpus cavernosum induced by the distension of the sinusoidal space or by the pelvic nerve electrostimulation was 69.6 +/- 14.4% (mean +/- SD).

Human Penile Hemodynamics Studied by a Polarographic Method

Observations of the tissue oxygen tension alteration were made using an open tip type oxygen electrode polarographic method as an index of blood flow change in the penile skin, corpus cavernosum and thigh skin of 16 males aged 20-26 years (average age: 20.5 years). In another five males aged 18-21 (average age: 19.8 years) the relationship between corpus cavernosum tissue oxygen tension alteration and penile circumference change in the erection process was observed. This relation was obtained in the penile circulation model, and penile hemodynamics were ascertained. In the flaccid penis the corpus cavernosum contains low-oxygen blood and there is a blockade at the vascular tree in the corpus cavernosum. In the tumescence phase the blood flow of the corpus cavernosum increased suddenly by the relief of cavernosum vascular blockade. During the penile tumescence phase the increased inflow and outflow persisted in corpus cavernosum, and in penile skin the blood also increased initially, but gradually decreased as penile circumference increased. After erection was attained it is thought that resistance to inflow occurred by outflow pathway contraction. In the detumescence phase, a decrease of inflow and a concomitant increase of outflow occurred and the reopening of outflow is thought to be necessary for prompt penile detumescence.

Antitumor effects of oral administration of an interferon-inducing pyrimidinone, Bropirimine, on murine renal-cell carcinoma

Bropirimine [2-amino-5-bromo-6-phenyl-4-(3H)-pyrimidinone] is a low-molecular-weight compound that acts as an inducer of interferon in several animal species. Experiments were designed to explore the possibility of using this drug for the treatment of renal-cell carcinoma (RCC). Euthymic BALB/c mice were inoculated with murine RCC (Renca) cells and given graded doses of Bropirimine p.o. for 5 consecutive days beginning on day 1 following tumor inoculation. These mice were killed and tumors were excised on day 21. Bropirimine significantly (P<0.01) inhibited the tumor growth at a daily dose of 1,000 or 2,000 mg/kg. No adverse effect or toxicity was noted at 1,000 mg/kg, and at 2,000 mg/kg there was only a marginal body-weight reduction without any other appreciable side effect. In addition to the inhibition of tumor growth, there was a small yet significant (P<0.05) increase in the duration of survival (in days) in the Bropirimine-treated animals. When the treatment was delayed to begin on day 6 following tumor inoculation, Bropirimine did not suppress tumor growth in euthymic mice, pointing to the importance of the timing of the treatment. In athymic nude BALB/c mice lacking T-cells or T-cell function, Bropirimine also inhibited tumor growth (P<0.01). The antitumor effect of this drug was abolished by pretreatment with anti-asialo GM1 serum, which eliminated natural killer (NK) activity in euthymic mice. In vivo treatment with Bropirimine augmented the cytotoxicity of lymphocytes isolated from the spleens or lungs of the tumor-bearing mice, which were active against Renca and YAC-1 cells in vitro. This activity was NK-cell-dependent as judged on the basis of the results of the in vitro complement-dependent cytotoxicity assay. Since Bropirimine induced interferon (IFN)-α/β production, significantly (P<0.05) elevating its serum concentration, and since this drug mimics the effects of IFN-α/β, it seemed likely that the Bropirimine-induced NK cell augmentation we found was mediated by IFN-α/β. These results suggest that Bropirimine, a booster of NK activity, may have potential as an adjunct to other therapeutic modalities in the treatment of human RCC.

Interleukin-2 Expanded Tumor-Infiltrating Lymphocytes and their Response to Preoperative α-Interferon in Patients with Renal Cell Carcinoma

To determine whether interferon-alpha could augment antitumorigenic effect of the tumor-infiltrating lymphocytes expanded with interleukin-2, we evaluated the properties of interleukin-2 expanded tumor-infiltrating lymphocytes in 24 patients with renal cell carcinoma with or without treatment with interferon-alpha. Tumor-infiltrating lymphocytes containing tumor cells were separated from nephrectomy specimens by enzymatic digestion and Percoll gradient centrifugation, and were cultured in the serum-free medium containing interleukin-2. The number of lymphocytes increased by 10 to 1,000-fold by day 28 of culture. There was no difference in the proliferation of tumor-infiltrating lymphocytes between interferon-alpha treated patients and controls. On day 14 tumor-infiltrating lymphocytes in the treated patients contained significantly more activated cells (HLA-DR+) and suppressor T cells (CD8+11+) than those in the controls. No significant difference was noted, however, in the cytotoxicity of tumor-infiltrating lymphocytes against autologous and allogenic renal cell carcinoma, K-562 or Daudi cells between the experimental and control groups on day 14 or 28. No specific effects on the major histocompatibility antigens, such as modulation of the expression attributable to the preoperative treatment with interferon-alpha, were observed on renal cell carcinoma tissue when determined by immunohistochemical staining. These findings suggest that interferon-alpha does not consistently produce a beneficial effect on interleukin-2 expanded tumor-infiltrating lymphocytes in patients with renal cell carcinoma.

Prostatic epithelial polyp of the prostatic urethra.

Ten cases of prostatic epithelial polyps of the prostatic urethra are reported. The ages of the patients were from 27 to 69 years, with a mean of 44 years. The most common clinical signs were gross hematuria, microhematuria, hematospermia, and dysuria. All specimens, obtained by transurethral resection, had a papillary or polypoid configuration. The tissue had a glandular structure that resembled that of the prostate. Prostate-specific antigen and prostatic acid phosphatase were found in the epithelial cells of the polyps by indirect immunoperoxidase staining. The polyps seemed to be hyperplasia of prostate-specific antigen and prostatic acid phosphatase-positive epithelial cells of the prostatic gland or duct, especially that of the latter.