bropirimine and Carcinoma--Transitional-Cell

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

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

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

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