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The pharmacokinetics of tamsulosin hydrochloride in patients with renal impairment were compared with those in healthy volunteers, and the factors that influenced plasma levels of tamsulosin were elucidated. A single oral dose of 0.2 mg of tamsulosin was given and blood and urine samples were obtained for 36 hours after administration. Unbound plasma concentration of tamsulosin was measured by a combination of equilibrium dialysis and liquid chromatography tandem mass spectrometry methods to examine the effect of protein binding on the pharmacokinetics of tamsulosin. Mean values for maximum concentration (Cmax) and area under the concentration-time curve (AUC) of total drug (Cmax,t and AUC1) in patients with renal impairment were 73% and 211% greater, respectively, than those in healthy volunteers. Mean Cmax and AUC of unbound drug (Cmax,u and AUCu), however, were almost the same in the two groups. A high correlation was found between alpha 1-acid glycoprotein (alpha 1-AGP) concentration and AUCt, but no correlation was found between alpha 1-AGP concentration and AUCu,0-36) or between creatinine clearance (ClCR) and AUCu,0-36). These results show that in patients with renal impairment, the pharmacokinetics of tamsulosin are affected by the change in protein binding that is associated with alteration of plasma alpha 1-AGP concentration, but are not largely affected by the decrease in the renal excretion. Although total tamsulosin levels increased as plasma protein binding increased, unbound tamsulosin levels (which are directly associated with the pharmacologic effects) remained unchanged in these patients.

Background: Intravesical instillation therapy of Bacillus Calmette-Guérin (BCG) has become a standard treatment for carcinoma in situ (CIS) of the urinary bladder. However, there have been few reports concerning the direct effect of BCG on existing tumors classified as Ta or T1. In the first stage of this clinical study, 157 patients were treated with BCG intravesical instillation (Tokyo 172 strain [BCG Co. Ltd., Tokyo, Japan]; 80 mg weekly for eight times) by our Study Group. The efficacy on existing tumors was a complete response (CR) rate of 84.4% and 66.4% and a partial response (PR) of 6.3% and 20.8% for 32 cases of CIS and 125 cases of Ta or T1 tumors, respectively., Methods: In the second stage of this study, the authors investigated the outcome of the 138 patients who had achieved CR or PR in the first stage. One hundred twenty (87.0%) of the patients were followed fully. Of those patients, 52 were randomized to receive prophylactic (maintenance) therapy consisting of BCG of 40 mg monthly for 12 times (Group A), whereas 55 were randomized to an untreated control group (Group B). Thirteen other patients refused to be randomized and were followed without prophylactic instillation., Results: The median follow-up period was 48 months for Group A and 42 months for Group B. In Groups A and B, the beneficial effect of the BCG therapeutic instillation persisted for a long time, and the 3-year nonrecurrence rate was 77.6% in Group A and 74.2% in Group B. Disease progression was observed rarely., Conclusion: For patients in whom transurethral resection of tumors of the bladder (TUR-Bt) alone is unlikely to eliminate the tumor, intravesical BCG is potentially the treatment of choice.

Background: Antitumor effects of Bacillus Calmette-Guérin (BCG) against superficial urinary bladder cancer is known to be strong when BCG is directly infused into the bladder cavity. For expression of that effect, attachment of BCG to tumor cells is reported to be essential as the first step. Our study was conducted to elucidate the significance of attachment of BCG to tumor cells in inducing the antitumor effect., Methods: BCG, Tokyo 172 strain, in the form of live bacilli, lyophilized bacilli, or autoclaved bacilli was co-cultured with MBT-2, mouse-origin transitional cell cancer cells. Various preparations of BCG were mixed with MBT-2 cells and transplanted to male C3H/He mice to see tumor growth-inhibiting effect., Results: Both live and lyophilized BCG attached strongly to MBT-2 cells. The maximal attachment to the cells with live BCG occurred 24 hours earlier than with lyophilized BCG. When BCG was autoclaved, it lost the ability to attach to the cells. Lyophilized or autoclaved BCG exerted a marked tumor growth-inhibiting effects. This effect was equal to the Tokyo 172 strain and the Armand Frappier Canada strain. Histologically, a high degree of infiltration by macrophages was seen., Conclusions: The results indicated that coexistence of BCG, even as killed by autoclaving, with tumor cells activates local immunity. Accordingly, the significance of the attachment of BCG to tumor cells in intravesical infusion therapy is surmised to lie in the fact that it results in retention of the BCG at the reaction site. This may provide a clue on how to approach future development of safer and more stable BCG-derived antitumor drugs.

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was administered intraperitoneally in combination with multidrug chemotherapy using methotrexate (M), vinblastine (V), doxorubicin (A), and cisplatin (C, or for the combination, MVAC) to C3H/He mice (5-week-old females) after experimental carcinoma, MBT-2, a transplantable transitional cell carcinoma of the urinary bladder had been implanted. The effects of therapy were studied. The animal groups consisted of: (1) control (no drug administration), (2) rhG-CSF (100 micrograms/kg/d, from days 8 through 42 after MBT-2 implantation, except for the days when MVAC was administered), (3) high-dose MVAC (2 mg/kg of M, 0.2 mg/kg of V, 2 mg/kg of A, and 4 mg/kg of C once a week for 3 weeks), (4) low-dose MVAC (one-quarter of the high dose), (5) high-dose MVAC with rhG-CSF, and (6) low-dose MVAC with rhG-CSF. In an in vitro system, rhG-CSF did not show any effect on the proliferation of MBT-2 cells or exert any influences on A's tumor proliferation-suppressing action on MBT-2. However, in an in vivo system, concomitant administration of rhG-CSF significantly enhanced the tumor-suppressing effect of the MVAC therapy, as did rhG-CSF alone. The greatest effect was observed in the group receiving high-dose MVAC plus rhG-CSF. These result suggested that rhG-CSF-stimulated granulocytes may exert antitumor activity on tumor cells severely damaged by chemotherapeutic agents at a relatively high concentration. The survival rate was improved to some degree even by administration of rhG-CSF alone. Although further study is required to elucidate the action mechanism of rhG-CSF, these results suggest that rhG-CSF may be useful clinically to enhance the activity of antitumor agents and not only through its ability to alleviate granulocytopenia or prevent its development.

The authors investigated the influences of recombinant human growth hormone (rh-GH) on rat urinary bladder carcinogenesis induced with N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Rats belonging to the control group (Group I, n = 19) were given 0.05% BBN in drinking water for 9 weeks, and the bladder was excised on the 22nd week after the initiation of BBN administration and inspected. All animals developed visible tumors in the bladder. The mean number of tumors per bladder was 11.26 +/- 5.21, and the mean total volume of tumors per bladder was 126.1 +/- 212.7 microliters. In all but one of the experimental groups (Group V) and in the control group, all animals developed visible tumors in the bladder. When 0.5 units of rh-GH was injected subcutaneously once a week from the week 1 through the week 6 (Group II; n = 20), the mean number of tumors and mean total volume of the tumors were 12.15 +/- 6.59 and 206.6 +/- 318.0 microliters, respectively. When the administration period of rh-GH was changed to between week 7 through the week 12 (Group III; n = 19), the mean number of tumors and mean total volume of the tumors were 16.95 +/- 7.07 and 204.5 +/- 317.7 microliters, respectively. When rh-GH was administered from the week 13 through the week 18 (Group IV; n = 19), the respective values were 16.79 +/- 10.75 and 213.4 +/- 274.6 microliters. In Group V (n = 19), which received only rh-GH from week 1 through the week 6, no tumors were detected. There were statistically significant differences in the mean tumor numbers between Groups I and III, Groups I and IV, and Groups II and III. The mean volume of individual tumor was the greatest in Group II, although the differences were not statistically significant in comparison with the other groups. Histologically, all tumors were transitional cell carcinoma in every group. There were no statistically significant differences in distributions of tumor stage and tumor grade between any groups. These findings suggest that rh-GH enhances the promotion of carcinogenesis of chemically induced rat urinary bladder cancer. It will be necessary to elucidate whether this effect of rh-GH is expressed by the somatostatin hypothesis of GH action, its direct action, or some other mechanisms.

A new bisphosphonate, 4-amino-1-hydroxybuthylidene-1,1-bisphosphonate (AHBuBP), was compared with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (AHPrBP) and 1-hydroxyethylidene-1,1-bisphosphonate (HEBP) in terms of its effect on tumor-induced osteolysis using a bladder tumor in mice (MBT-2). Tumor cells were inoculated subcutaneously (SC) over the calvaria in mice, resulting in a local tumor causing fragmentation of the bone. The tumor-induced osteolysis associated with osteoclasts proliferation was accompanied with reactive new bone formation. This osteolysis was evaluated by measuring the increased area of bone resorption in reduced opacity to radiograph and histologic study. The results showed the following sequence of potency: AHBuBP greater than AHPrBP = HEBP. This inhibition was obtained with no apparent effect on the growth of the MBT-2 tumor. The authors conclude that AHBuBP appears to be an interesting new bisphosphonate with possible clinical application.

Forty-six patients with adenocarcinoma of the prostate were given an intravenous infusion of the thymidine analogue, bromodeoxyuridine (BrdU), 200 mg/m2, at the time of needle biopsy or transurethral resection to label tumor cells in the DNA synthesis phase. The tumor specimens were stained by an indirect immunoperoxidase method with anti-BrdU monoclonal antibody. The BrdU labeling index, S-phase fraction, was determined by counting the number of BrdU-labeled cells in the tissue sections. S-phase fraction correlates with the results of histologic tumor grade, Gleason score, and growth patterns. The higher S-phase fraction may indicate biologic malignancy. Moreover, the degree of heterogeneity concerning S-phase fraction distribution within prostate cancer tissue could be evaluated and the findings compared with the morphologic appearance. The authors results suggest that the measurement of BrdU labeling index in prostate cancer may prove to be a new objective and quantitative assay for biologic potential of individual tumors.

Clinical evaluation of 460 cases of urothelial tumors of the renal pelvis and ureter was performed using a new clinical classification system, since no systemic clinical classification such as the TNM system for bladder tumors has been available to date. ABC, and TS and TE categories were newly adopted. The former distinguishes tumor multicentricity, and the latter indicates the clinical tumor stage. Tumors arising in one organ and homolaterally are categorized as A, while those in both organs (ureter and renal pelvis) and/or in the bladder are B, and bilateral tumors are C. TS represents the tumors of pT1 and pT2, and TE represents pT3, and pT4. Tumors belonging to pB showed a poorer prognosis than pA tumors. The TS and TE staging system clearly reflected the histopathologic stage, and produced significant differences in relative survival rates. Regarding various prognostic factors, our series gave the same results as reported by other investigators. However, it should be stressed that female patients showed a poorer prognosis than male patients.

Tumor-bone interactions were experimentally studied using four transplantable human urogenital tumors in nude mice. The method consisted of subcutaneously (SC) inoculating tumor cells over the calvaria in nude mice after the periosteum has been disrupted. This resulted in a local tumor causing fragmentation of the bone. The degree of tumor-bone interaction also varied with the type of implanted tumors as shown in radiographic and histologic examinations. All tumors were associated with histologic patterns of classical bone remodeling, including bone destruction with osteoclast proliferation and reactive new bone formation. The evidence presented here suggests that the majority of tumor-bone interaction showed a combination of both features, bone destruction and new bone formation, and the mechanisms whereby tumors interact with bone may vary with the biological properties of the tumor. Our new system would be suitable for studying the biology of local interaction between bone and tumor cells and searching out a method to protect the bone from cancer cells.

The effects of intravesical instillation of Adriamycin (doxorubicin) (ADR), and mitomycin C (MMC), as inhibitors of development of rat bladder tumors, were examined in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Intravesical instillation of ADR or MMC once a week for 12 weeks into rats pretreated with BBN for 4 weeks markedly enhanced development of bladder tumors. That is, one week after the end of intravesical instillation of these compounds the incidence of papillary or nodular hyperplasias, namely preneoplastic lesions, was significantly increased, and at the end of the experiment the incidence of not only papillary or nodular hyperplasias but also of papillomas and cancers was significantly increased. These results indicate that the intravesical instillation of ADR or MMC promotes two-stage bladder carcinogenesis in rats.