bropirimine and Urinary-Bladder-Neoplasms

Bladder cancer treatment remains a challenge despite significant improvements in preventing disease progression and improving survival. Intravesical therapy has been used in the management of superficial transitional cell carcinoma (TCC) of the urinary bladder (i.e. Ta, T1, and carcinoma in situ) with specific objectives which include treating existing or residual tumor, preventing recurrence of tumor, preventing disease progression, and prolonging survival. The initial clinical stage and grade remain the main determinant factors in survival regardless of the treatment. Prostatic urethral mucosal involvement with bladder cancer can be effectively treated with Bacillus Calmette-Guerin (BCG) intravesical immunotherapy. Intravesical chemotherapy reduces short-term tumor recurrence by about 20%, and long-term recurrence by about 7%, but has not reduced progression or mortality. Presently, BCG immunotherapy remains the most effective treatment and prophylaxis for TCC (Ta, T1, CIS) and reduces tumor recurrence, disease progression, and mortality. Interferons, Keyhole-limpet hemocyanin (KLH), bropirimine and Photofrin-Photodynamic Therapy (PDT) are under investigation in the management of TCC and early results are encouraging. This review highlights and summarizes the recent advances in therapy for superficial TCC.

Topics: Administration, Intravesical; Antineoplastic Agents; BCG Vaccine; Carcinoma, Transitional Cell; Cytosine; Dihematoporphyrin Ether; Hemocyanins; Humans; Interferons; Photochemotherapy; Secondary Prevention; Urinary Bladder Neoplasms

Topics: Adjuvants, Immunologic; Administration, Intravesical; Administration, Oral; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Bacterial Vaccines; Carcinoma, Transitional Cell; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cytosine; Exotoxins; Heart Diseases; Hemocyanins; Humans; Immunologic Factors; Immunotherapy; Interferons; Interleukins; Randomized Controlled Trials as Topic; Recombinant Proteins; Transforming Growth Factor alpha; Treatment Outcome; Tumor Necrosis Factor-alpha; Urinary Bladder Neoplasms

Bacillus Calmette-Guerin (BCG) has been shown to be the most effective agent for the treatment of superficial bladder cancer since its approval by the US Food and Drug Administration for the treatment of carcinoma in situ of the bladder in 1990. Recently, augmentation of BCG immunotherapy with interferon-alpha2b and other agents is emerging as salvage therapy for those patients who fail initial treatment. This review summarizes the role of various immunotherapeutic agents in the treatment of bladder cancer, with special emphasis on the appropriate administration and schedule of BCG therapy as well as salvage with the combination of BCG with interferon-alpha2b.

Topics: Adjuvants, Immunologic; Antineoplastic Agents; BCG Vaccine; Carcinoma in Situ; Cytosine; Drug Administration Schedule; Garlic; Humans; Interferon alpha-2; Interferon-alpha; Interleukins; Plant Extracts; Prognosis; Recombinant Proteins; Salvage Therapy; Urinary Bladder Neoplasms; Vitamins

To explore new treatment strategies in high-risk superficial bladder cancer patients, such as recurrent carcinoma in situ (CIS) or pT1 transitional cell carcinoma after intravesical bacillus Calmette-Guérin (BCG).. Mechanism of action, pharmacology and the results of clinical phase I and II trials with the oral biological response modifier bropirimine are reviewed.. In a phase II trial in which CIS patients were treated, 17 complete responses were seen in 29 patients (59%) at the 3,000-mg dose level. Moreover, this trial indicated that bropirimine is a promising alternative in BCG recurrent or BCG intolerant patients: in 13 BCG failures, 6 complete responses were seen. Side effects are mild to moderate, mainly flu-like symptoms.. These results suggest that bropirimine is effective at 3,000 mg/day, and that patients with prior BCG therapy may be salvaged by bropirimine treatment.

Topics: Adjuvants, Immunologic; Antineoplastic Agents; Carcinoma in Situ; Clinical Trials as Topic; Cytosine; Dose-Response Relationship, Drug; Humans; Neoplasm Recurrence, Local; Urinary Bladder Neoplasms

Bropirimine has been shown to have activity against carcinoma in situ (CIS) of the bladder in a previous phase-I trial. A review of three completed clinical trials as well as ongoing studies is presented to provide a current update.. Details of the initial phase-I trial are reviewed, as are findings of a subsequent phase-II trial in bladder CIS and a multicenter study in upper tract CIS. All have used a dose of 3 g/day for 3 consecutive days each week, repeated weekly for up to 1 year. Cytology must be positive prior to treatment, and both biopsies and cytology must be negative after therapy for the patient to be considered a complete response.. In the phase-II trial in bladder CIS, 20 (61%) of 33 patients had a complete response. Responders included patients with prior bacillus Calmette-Guérin (BCG) therapy, uni- and multifocal CIS, and primary and secondary CIS. Responses were seen in 10 (48%) of 21 evaluable patients with upper tract CIS. Toxicities in both studies were manageable in most patients. Trials underway include bropirimine in BCG-failed CIS, a randomized comparison to BCG in previously untreated patients, and a trial of the two together.. Bropirimine does have activity against both bladder and upper tract CIS on the dose schedule used to date.

Topics: Adjuvants, Immunologic; Antineoplastic Agents; Carcinoma in Situ; Clinical Trials as Topic; Cytosine; Humans; Immunotherapy; Neoplasm Recurrence, Local; Ureteral Neoplasms; Urinary Bladder Neoplasms

There are theoretical limits to the efficacy of intravesical chemotherapy for prevention of tumor recurrence after transurethral resection of a superficial bladder cancer. Our multi-institutional studies revealed that the direct efficacy of BCG, intravesical instillation for treatment of an existing tumor is very promising. This efficacy persisted over a long period of time, and the subsequent recurrence rate was markedly reduced. Bladder cancer, sometimes earlier known as an occupational disease, might be related to unknown chemical carcinogens. Since enterobacterias are thought to produce carcinogens and mutagens, including nitroso-compounds in the intestinal tract, BLP (lactobacillus casei preparation), treatment may suppress the production of such compounds by altering the intestinal flora. Preclinical studies have demonstrated that BLP suppresses the development of bladder cancer induced by N-butyl-N-(4-hydroxy-butly)-nitrosamine in mice and rats. A double-blind clinical trial recently revealed that BLP was effective for preventing the recurrence of superficial bladder cancer. Bropirimine, a interferon inducer, is now an internationally developing agent for superficial bladder cancer, which is discussed on the basis of Japanese phase II trial data.

Topics: Administration, Intravesical; Animals; BCG Vaccine; Butylhydroxybutylnitrosamine; Carcinoma, Transitional Cell; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Cytosine; Humans; Interferon Inducers; Mice; Multicenter Studies as Topic; Neoplasm Recurrence, Local; Rats; Urinary Bladder Neoplasms

Interleukin-2, IFNs, and TNF are biologic response modifiers that are part of an intricate network of interacting cytokines released during an immune response. Lack of sufficient endogenous cytokine activity secondary to the immunosuppressive effects of tumor growth may be overcome by direct, local application of biologic response modifiers or immunostimulants such as BCG or KLH. Bacillus Calmette-Guérin remains the most effective immunotherapeutic agent for superficial transitional-cell carcinoma. Although the mechanism of action is unknown, the weight of evidence suggests that local cytokine release is involved in the effector pathway. Recent data have shown that the local application of new single-agent immunotherapies can have an effect on superficial transitional-cell carcinoma and CIS similar to that of chemotherapeutic agents and nearly identical to that of BCG. But, unlike the situation with chemotherapy or BCG, these effects are attended by minimal or no toxicity. Chemotherapy and BCG failures have also shown responses to direct instillation of cytokines. Further understanding of the exact mechanism of action of these agents and of their interaction should lead to the optimal antitumor regimen with the least toxicity. Determining the degree of host immunoresponsiveness and which combination of cytokines or immunotherapeutic or chemotherapeutic agents is most effective for a specific tumor type is the challenge for the future.

Topics: Adjuvants, Immunologic; Carcinoma, Transitional Cell; Cytosine; Hemocyanins; Humans; Interferon Inducers; Interferons; Interleukin-2; Tumor Necrosis Factor-alpha; Urinary Bladder Neoplasms

This European phase III clinical trial was part of an intercontinental study which was closed prematurely by the sponsor. The study was designed to compare the effects of oral bropirimine with intravesical BCG, the current standard treatment in patients with newly diagnosed bladder carcinoma in situ (CIS).. A total of 55 BCG-naive patients with bladder CIS were randomized to receive bropirimine (n = 27) or BCG (n = 28). Bropirimine was orally administered at a dose of 3 g/day for 3 consecutive days with a 4-day drug-free interval for up to 1 year. BCG-Tice instillations were administered weekly for 2 x 6 weeks. Both biopsies and cytology had to be negative for the patient to be considered a complete responder (CR).. The percentage of dropouts for all of the adverse events was 4% for bropirimine and 14% for BCG. The most frequently reported local events in the bropirimine- versus the BCG-treated group were irritative complaints, 64 vs. 89% (p = 0.03) and hematuria, 24 vs. 61% (p < 0.01). The most frequently reported systemic events in the bropirimine- versus the BCG-treated group were fever 4 vs. 21%, flu syndrome 24 vs. 7%, headache 28 vs. 11% and nausea 24 vs. 11% (all p > 0.05). A total of 92% of the patients treated with bropirimine had a CR with a mean duration of 12.6 months (95% CI 9.2-15.9). In the BCG group, all of the patients had a CR with a mean of 12.3 months (95% CI 8.5-16.0).. This study shows that bropirimine, an orally administered drug that can be self-administered to outpatients with more acceptable local toxicity compared to BCG, could be an effective first-line therapy in patients with CIS of the urinary bladder. Continued investigation of bropirimine is warranted to increase its clinical utility.

Topics: Adjuvants, Immunologic; Administration, Oral; BCG Vaccine; Carcinoma in Situ; Chi-Square Distribution; Cytosine; Female; Humans; Male; Survival Rate; Treatment Outcome; Urinary Bladder Neoplasms

A follow-up investigation was conducted on a Late Phase II clinical study of bropirimine for carcinoma in situ (CIS) of the bladder. We previously reported that 48 patients were enrolled and 17 patients achieved complete remission (CR) in the Late Phase II study. Of the 17 CR patients, 5 had recurrence, but 9 were recurrence free for a year and 5 have remained so for more than 2 years (median follow-up: 29.1 +/- 4.2 months). The 1-year and 2-year recurrence-free rates calculated using the Kaplan-Meier method were 70.3% and 61.5% respectively. Of all the 47 bropirimine-treated patients, 11 underwent total cystectomy (median follow-up: 31.8 +/- 5.2 months). The rates of bladder preservation after 1 year, 2 years, and 3 years calculated using the Kaplan-Meier method were 87.2%, 80.7%, and 74.0% respectively. Of the 39 patients who did not respond to bropirimine or suffered from recurrence after bropirimine treatment, 19 received subsequent intravesical bacillus Calmette-Guerin (BCG) therapy and 13 achieved CR (68.4%). This suggests that bropirimine does not decrease the efficacy of BCG therapy. In the present study, the prognosis was confirmed to be favorable after bropirimine therapy. Bropirimine would thus seem to be a useful oral anticancer agent for bladder CIS.

Topics: Administration, Intravesical; Administration, Oral; Antineoplastic Agents; BCG Vaccine; Carcinoma in Situ; Cytosine; Drug Administration Schedule; Follow-Up Studies; Humans; Urinary Bladder Neoplasms

Bropirimine is an oral immunomodulator that has demonstrated anticancer activity in transitional cell carcinoma in situ (CIS) in both the bladder and upper urinary tract. Activity also has been documented in patients after prior therapy with bacille Calmette-Guérin (BCG). To more accurately estimate bropirimine's efficacy in BCG-resistant bladder CIS, a Phase II trial was performed. A separate analysis was performed in additional patients intolerant of BCG toxicity.. Patients received bropirimine 3.0 g/day by mouth for 3 consecutive days, weekly, for up to 1 year. Bladder biopsies and cytologic examination were performed quarterly. Complete response (CR) required negative biopsy and cytology results.. Twenty-one of 86 patients entered were not evaluable. CR was seen in 21 (32%; 95th percentile confidence interval [CI], 21% to 44%) of 65 evaluable patients, including 14 (30%, CI 17% to 43%) of 47 BCG-resistant, and 7 (39%, CI 16% to 61%) of 18 BCG-intolerant patients. Overall, by intent-to-treat analysis, CR was thus seen in 21 (24%) of 86 subjects. Most BCG-resistant patients were failures to BCG without relapse, and had received 12 to 36 (median 12) BCG treatments; intolerant patients had received 4 to 11 treatments (median 6). Response duration ranged from 65 to 810 days, with median not yet reached (but greater than 12 months). Thirteen (15%) of 86 stopped bropirimine due to toxicity. Progression to invasive or metastatic disease during or immediately after therapy was documented in only 4 patients (6%), all nonresponders.. Bropirimine may be an alternative to cystectomy for some patients with bladder CIS who have failed or have not tolerated BCG. Further evaluation to improve responses and durability is warranted.

Topics: Adjuvants, Immunologic; Administration, Oral; BCG Vaccine; Carcinoma in Situ; Cytosine; Humans; Remission Induction; Treatment Failure; Urinary Bladder Neoplasms

Early Phase II clinical studies with bropirimine (U-54461S) having interferon (IFN) inducing and direct antiproliferative activities were conducted in patients with various solid tumors or hematologic neoplasm at 34 institutions nationwide. To investigate the safety and efficacy of the treatment, bropirimine was orally administered to the patients at the dose of 1g every two hours, three times a day for three consecutive days with a four day drug-free interval. Among the 65 patients registered, 60 patients were eligible and 44 patients completed bropirimine treatment in accordance with the respective protocols. Complete response (CR) was observed in 7 cases, and partial response (PR) was observed in 4 cases, so the efficacy rate was 25.0% (7 CRs + 4 PRs/44). Classified by target tumors, the efficacy rates were 12.9% (6 CRs/14) in bladder CIS, 33.3% 1 CR/3) in superficial bladder cancer. 11.1% 1 PR/9) in renal cell carcinoma, and 42.9% (3 PRs/7) in malignant lymphoma, respectively. Adverse drug reactions frequently observed were influenza-like symptoms such as fever (60.0%) and generalized malaise (21.7%), gastrointestinal symptoms like anorexia (56.7%) and nausea/vomiting (43.3%), and adverse effects on the circulatory system such as tachycardia (15.0%) and abnormalities in ECG (11.7%). Most of these symptoms were relieved or improved. Abnormalities in laboratory tests observed frequently were adverse effects on the liver such as elevations in GPT (33.3%), in GOT (31.7%), and in LDH (18.3%) or on the blood system like a decrease in RBC (18.3%), leukopenia (26.7%), or neutropenia (25.0%). In conclusion, bropirimine treatment proved to be effective for bladder CIS in particular, suggesting that it will be promising for use in the treatment of the disease.

Topics: Adult; Aged; Anorexia; Antineoplastic Agents; Cytosine; Drug Administration Schedule; Female; Fever; Hematologic Neoplasms; Humans; Interferon Inducers; Male; Middle Aged; Nausea; Skin Neoplasms; Urinary Bladder Neoplasms; Urologic Neoplasms; Vomiting

Late Phase II clinical study with bropirimine (U-54461S), a novel oral antitumor agent that has interferon inducing and anti-proliferative activities, was conducted in patients with bladder CIS at 38 institutions nationwide. To investigate the efficacy and safety of the treatment, bropirimine was administered to the patients at the dose of 750 mg every two hours, three times a day, for three consecutive days with four-day drug withdrawal, based on the results of the preceding clinical studies up to early phase II. Among the 48 patients registered, 41 patients were evaluable for antitumor efficacy. Complete response (CR) was observed in 17 of them, no change (NC) in 18 patients, and progressive disease (PD) in 6 patients; so the efficacy rate was 41.5%. Classified by patient background, the efficacy rates were 58.3% (7/12) in patients with primary bladder CIS, 34.5% (10/29) in those with secondary bladder CIS, 45.5% (10/22) in those with Grade 3, and 23.8% (5/21) in those previously given chemotherapeutic agents or BCG by intravesical or other routes. Adverse drug reactions frequently observed were influenza-like symptoms such as fever and generalized malaise and gastrointestinal symptoms like anorexia and nausea/vomiting; these symptoms were all Grade 2 or milder. Abnormalities in laboratory tests, such as an elevation in GOT/GPT, neutropenia, and leukopenia were observed. These adverse effects were all tolerated by the patients. From the above results, bropirimine was considered to be a useful oral agent for the treatment of bladder CIS.

Topics: Administration, Oral; Anorexia; Antineoplastic Agents; Carcinoma in Situ; Cytosine; Drug Administration Schedule; Fever; Humans; Interferon Inducers; Nausea; Urinary Bladder Neoplasms; Vomiting

Bropirimine is an orally administered immunostimulant that has been shown to have activity against carcinoma in situ (CIS) of the bladder. To further assess this potential activity, bropirimine was administered to 42 patients for bladder CIS in a Phase II trial.. Patients were treated with bropirimine 3.0 g/day by mouth for 3 consecutive days each week up to 1 year. Cystoscopy with biopsies and bladder wash cytology were performed quarterly.. Twenty (61%) of 33 evaluable patients converted malignant biopsies and bladder wash cytology to negative, including 6 (50%) of 12 who failed prior bacillus Calmette-Guérin (BCG) immunotherapy, 14 (67%) of 21 who had not received prior BCG therapy, and 12 (80%) of 15 with primary CIS. Median response duration exceeds 21 months. Four of the 20 responders did have a papillary tumor recurrence at 3 to 15 months, all Stage Ta or T1. Mild toxicity (grade I or II) suggestive to interferon induction or administration occurred in one third of patients. Headache, transient hepatic enzyme elevations, skin rash, and arthralgias each occurred in 5% to 14% of the patients, with nausea or emesis in 21%. Grade 1 tachycardia/palpitations or chest pain each were noted in 5%.. Oral bropirimine can induce remission of bladder CIS with acceptable toxicity at 3.0 g/day. Bropirimine may be a valuable alternative to cystectomy for some failures of BCG therapy and may have the potential to replace BCG as front-line therapy because of its ease of administration.

Topics: Adjuvants, Immunologic; Administration, Oral; Adult; Aged; Aged, 80 and over; Carcinoma in Situ; Cytosine; Female; Humans; Male; Middle Aged; Urinary Bladder Neoplasms

Topics: Antineoplastic Agents; BCG Vaccine; Carcinoma in Situ; Cytosine; Humans; Urinary Bladder Neoplasms

To investigate efficacy and safety of bropirimine, a new orally active interferon inducer, in patients with superficial bladder cancer.. Twenty patients with histologically confirmed recurrent superficial transitional cell carcinoma (Ta or T1) were studied. At least one marker lesion remained in all patients after transurethral resection. Bropirimine (750 mg) was given orally three times at 2-hour intervals (daily dose 2,250 mg) on 3 consecutive days weekly for 12 weeks.. Of the 17 evaluable patients, 1 did not complete the treatment protocol. There were 5 responders, including 2 with a complete response (complete disappearance of the marker tumor) and 3 with a partial response (>50% reduction of the marker tumor). The objective response rate was 31.3% (5/16; 95% confidence interval 11.0-58.7%) for the 16 patients completing treatment and 29.4% (5/17; 95% confidence interval 10.3-56.0%) for the 17 evaluable patients. Adverse reactions occurred in 70.6% of the evaluable patients. Flu-like symptoms were most common, including malaise (23.5%), headache (23.5), and fever (11.8%), followed by gastrointestinal symptoms including less of appetite (23.5%). All of these reactions were tolerable.. Bropirimine may be useful for the prophylaxis of recurrence following transurethral resection of superficial bladder cancer because it shows efficacy against marker tumors and has a good safety profile and oral activity.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Transitional Cell; Cytosine; Female; Humans; Interferon Inducers; Male; Middle Aged; Neoplasm Recurrence, Local; Treatment Outcome; Urethra; Urinary Bladder Neoplasms

Bropirimine is an antitumor agent currently used in clinical trials on bladder cancer. It is known to induce IFN, to activate NK cells and to inhibit the growth of tumor cells. In this study, we examined the in vitro and in vivo efficacy of bropirimine on human and murine bladder cancer. Bropirimine showed in vitro antiproliferative activity on the human bladder cancer cell lines, T 24 and KoTCC-1. This activity was not: affected by the neutralizing antibodies against IFN-alpha, TNF-alpha or IL-1 beta, indicating it is the direct activity of bropirimine without involvement of cytokine production by tumor cells. Bropirimine was active at the concentrations comparable to those in serum or urine attained in clinical trials, which suggests that this direct antiproliferative activity is one of the important antitumor mechanisms of bropirimine. In in vivo experiments, bropirimine reduced the growth of transplanted murine MBT-2 and human KoTCC-1 bladder cancers by oral administration every 4 days starting on day 1, but did not show efficacy when the drug treatment was started on day 8. The antitumor activity of bropirimine was dependent on the timing for drug treatment initiation.

Topics: Animals; Antineoplastic Agents; Cell Division; Cytosine; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Nude; Tumor Cells, Cultured; Urinary Bladder Neoplasms

A total of 34 patients with measurable superficial transitional cell cancer of the bladder entered into a phase 1, nonrandomized, noncomparative trial to assess the toxicity of the oral interferon inducer bropirimine. Of the patients 26 were also evaluable for response. The toxicity of bropirimine was minimal. At the 3-month evaluation 6 patients had experienced complete regression of tumor and had negative cytology studies, and 2 had partial responses. The majority of complete responses were in patients with carcinoma in situ only, with most responses seen at higher dose levels. One patient with papillary tumor and carcinoma in situ had a complete response. Some early responses appear to be durable. Most importantly, a high rate of complete response was noted at higher dose levels among patients who had failed prior therapy with bacillus Calmette-Guerin. Further clinical trials of bropirimine in bladder cancer appear warranted.

Topics: Administration, Oral; Antineoplastic Agents; Carcinoma in Situ; Carcinoma, Papillary; Carcinoma, Transitional Cell; Cytosine; Drug Evaluation; Humans; Urinary Bladder Neoplasms

Interferons (IFNs) have established activities as antivirals and inhibitors of viral and transplantable tumors. To establish whether IFNs or their inducers can affect induction of carcinogenesis in vivo, the bladder-specific carcinogen N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) was administered in the diet at 0.11 or 0.13% (w/w) to female C3H/He mice beginning at 7 weeks of age. Mice treated with the IFN-inducing bropirimine [2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone] i.p. twice a week for 14 weeks starting on day 30 of start of FANFT feeding developed fewer transitional cell carcinomas (TCC) than mice treated with the vehicle. Bropirimine (200 mg/kg twice a week) orally resulted in even greater effectiveness: 6 of 43 bladders with TCC for bropirimine-treated mice versus 24 of 39 for control glycine buffer-treated mice (P less than 0.01, x2 test). Mice treated i.p. daily on days 29 through 210 with 5,000 units of beta interferon (specific activity, 2.0 x 10(8) units/mg) had 0 of 15 TCC while control mice had 7 of 13 TCC (P less than 0.001). Bladders of untreated mice were also significantly heavier than those of beta interferon- or bropirimine-treated mice. This dose of IFN treatment was confirmed as effective in a second experiment, in which mice were treated daily on days 30-223 with 5,000 units alpha/beta interferon (specific activity, 1.2 x 10(7) units/mg). This resulted in 4 of 25 bladders with TCC versus 24 of 39 for control mice (P less than 0.001). A higher dose of IFN (50,000 units alpha/beta interferon daily) was toxic; 24 of 30 mice died within 2 months. IFN and an IFN inducer, bropirimine, inhibited development and progression of FANFT-induced bladder TCC in vivo and thus may have roles as chemopreventive modalities.

Topics: Animals; Antineoplastic Agents; Carcinoma, Transitional Cell; Cytosine; Drug Evaluation, Preclinical; FANFT; Female; Interferon Inducers; Interferon Type I; Mice; Mice, Inbred C3H; Urinary Bladder Neoplasms