Combination Immunotherapy of Murine Transitional Cell Cancer Using BCG and an Interferon-Inducing Pyrimidinone

Abstract

The immunomodulator ABPP (2-amino-5-iodo-6-phenyl-4(3H) pyrimidinone) is an interferon inducer and has been shown to have in vivo activity against the murine bladder tumor MBT-2. Two experiments were performed to determine if ABPP might enhance the in vivo anti-tumor activity of Bacillus Calmette-Guerin (BCG). First, in vivo stimulation of cell-mediated cytotoxicity by BCG and ABPP was measured in C3H mice using a chromium-release assay. An earlier, greater, and longer-lasting increase in cytotoxicity was caused by ABPP than by BCG. Based on the differing times to peak cytotoxic stimulation, groups of 15 mice each were pretreated intraperitoneally at different times prior to inoculation with MBT-2. Compared to saline, ABPP alone did not increase survival, while BCG alone did increase survival (p less than 0.01), and the combination of BCG and ABPP yielded the highest survival (p less than 0.001). These results indicate that 1) ABPP affects the immune system differently than BCG, and 2) while ABPP may have less single-agent activity against MBT-2 than BCG, ABPP may serve to potentiate the activity of BCG.

Oral Bropirimine Immunotherapy of Rodent Prostate Cancer

“…The two cell lines showed a stronger anticancer effect than was seen in several in vivo studies in the murine bladder cancer MBT-2 which led to the clinical evaluation of bropirimine in human bladder cancer [11][12][13], There was no survival…”

A Review of Clinical Studies of Bropirimine Immunotherapy of Carcinoma in situ of the Bladder and Upper Urinary Tract

“…BCG is given on Mondays and treatment with bropirimine is self-administered by the patients at home on Wednesday, Thursday, and Friday evenings. This study is based upon the results of the murine study which suggest ed that synergism occurred when BCG and bropirimine were used in combination [17]. To date, 25 patients have been entered and the trial is temporarily closed to accrual to determine whether sufficient responses exist to warrant continued enrollment to the full phase-II trial size of 42 patients.…”

“…We initially compared these compounds to BCG by measuring induction of cellmediated cytotoxicity in peritoneal exudate cells in C3H mice. After finding that the interferon-inducer bropirim ine produced a stronger and longer lasting stimulation of peritoneal exudate cell cytotoxicity than BCG, a series of in vivo studies using the murine bladder tumor MBT-2 was performed [17], These led to a series of clinical stud ies in bladder and upper urinary tract CIS that are reviewed herein.…”

Interferons in the Therapy of Solid Tumors

“…Other potential approaches would be to combine IFN and BCG or chemotherapeutic agents. The immunomodulator ABPP (2-amino-5-iodo-6-phenyl-4-pyrimidine), which acts as an IFN inducer, has in fact been shown to enhance the activity of BCG against the murine bladder tumor MBT-2 [75]. Preliminary results of a study combining IFN-a and mitomycin C for superficial bladder cancer suggest that the combination may be more effective than either agent alone [76],…”