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Antitumor effects of polyribonucleotides for mouse transitional cell carcinoma enhanced by cyclophosphamide
Abstract:
Mouse bladder tumor (MBT-2), derived from a carcinogen-induced transitional cell carcinoma of the bladder, has proven a useful model for study of pathogenesis and prediction of cytotoxic drug sensitivity of human bladder carcinoma. To define optimal conditions for activity of the potent interferon inducer polyriboinosinic-polyribocytidylic acid [poly(I) X poly(C)] in this model, studies of dose, timing, and combinations with a cytotoxic drug were initiated. Poly(I) X poly(C) inhibited MBT-2 growth when 10(5) or 10(6) tumor cells were implanted. Tumor growth reduction was relatively more pronounced in mice inoculated with higher numbers of MBT-2 cells (10(6] than in mice inoculated with an intermediate dose (10(5] or small dose (10(4]. In mice inoculated with 10(5) MBT-2 tumor cells, poly(I) X poly(C) (2.5 or 10 mg/kg i.p.) on Days 5 to 19 every other day reduced tumor size markedly. It had no effect, however, on tumor incidence or the time of their first detection. Treatment for a shorter period (alternate days from Days 11 to 19) resulted in less inhibition of tumor growth. Once treatment was discontinued, tumors grew progressively. Polyriboadenylic:polyribouridylic acid [poly(A) X poly(U)] (10 mg/kg) which inhibited tumor growth but to a lesser degree than poly(I) X poly(C) induced lower, less sustained levels of serum interferon. Cyclophosphamide, injected i.p. on Day 1, resulted in inhibition of tumor incidence and growth in direct proportion to the dose administered (25 to 200 mg/kg), but it was curative only at greater than or equal to 30% lethal doses. When combined with poly(I) X poly(C) (2.5 or 10 mg/kg), cyclophosphamide (50 mg/kg) had an additive antitumor effect. Optimal inhibition of MBT-2 tumor growth occurred by combining cyclophosphamide (100 mg/kg) with poly(I) X poly(C) (2.5 mg/kg); eight of 14 mice were tumor free on Day 60.
Insights
This study optimized polyriboinosinic-polyribocytidylic acid [poly(I) X poly(C)] treatment in a mouse bladder tumor model. Combining poly(I) X poly(C) with cyclophosphamide showed optimal antitumor effects, leading to tumor remission in some mice.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- The mouse bladder tumor (MBT-2) model, derived from transitional cell carcinoma, is valuable for studying bladder cancer pathogenesis and drug sensitivity.
- Polyriboinosinic-polyribocytidylic acid [poly(I) X poly(C)] is a potent interferon inducer with potential antitumor activity.
- Optimizing the use of poly(I) X poly(C) in the MBT-2 model requires defining ideal conditions for its administration.
Purpose of the Study:
- To determine the optimal dose, timing, and combination therapy for polyriboinosinic-polyribocytidylic acid [poly(I) X poly(C)] in the mouse bladder tumor (MBT-2) model.
- To evaluate the efficacy of poly(I) X poly(C) alone and in combination with cyclophosphamide against MBT-2 tumors.
- To assess the impact of treatment on tumor incidence, growth, and survival.
Main Methods:
- MBT-2 cells were implanted in mice at varying doses (10(4) to 10(6) cells).
- Polyriboinosinic-polyribocytidylic acid [poly(I) X poly(C)] was administered at different doses (2.5 or 10 mg/kg) and schedules (Days 5-19 every other day).
- Combinations of poly(I) X poly(C) with cyclophosphamide were tested, and tumor growth, incidence, and survival were monitored.
Main Results:
- Polyriboinosinic-polyribocytidylic acid [poly(I) X poly(C)] inhibited MBT-2 tumor growth, with greater effect at higher cell inoculums.
- Optimal inhibition was achieved with poly(I) X poly(C) administered from Day 5 to 19, but it did not affect tumor incidence.
- Combining cyclophosphamide (100 mg/kg) with poly(I) X poly(C) (2.5 mg/kg) resulted in optimal antitumor activity, with 8 of 14 mice tumor-free by Day 60.
Conclusions:
- Polyriboinosinic-polyribocytidylic acid [poly(I) X poly(C)] demonstrates significant antitumor activity in the MBT-2 mouse bladder tumor model.
- Combination therapy with cyclophosphamide enhances the antitumor efficacy of poly(I) X poly(C).
- The optimal combination regimen holds promise for treating bladder carcinoma, warranting further investigation.