Quinidine, which has antiarrhythmic activity, greatly enhanced the cytotoxicity of vincristine (VCR) in tumor cells and especially in VCR-resistant sublines of P388 leukemia (P388/VCR) and human myelogenous leukemia. A nontoxic concentration of quinidine increased VCR cytotoxicity in these resistant tumor cells about 50 to 80 times, and the drug in combination with VCR could completely reverse VCR resistance of these cell lines. Quinidine also enhanced the cytotoxicity of Adriamycin, especially in the Adriamycin-resistant subline of P388 leukemia; this enhancement (8-fold) was less than that of VCR toxicity in the VCR-resistant tumor line. When administered daily for 10 days with VCR, quinidine at doses of 50 to 125 mg/kg significantly enhanced the chemotherapeutic effect of VCR in P388/VCR-bearing mice. Some other antiarrhythmic agents also showed similar effects in vitro, but these effects were considerably lower than that of quinidine. Quinidine increased the cellular levels of VCR and daunomycin in VCR-resistant sublines of mouse and human tumors and the ADM-resistant mouse tumor line in vitro, respectively. Quinidine also enhanced the cellular accumulation of VCR in P388/VCR cells in vivo. Thus, the therapeutic effect observed in P388/VCR-bearing mice might be due to the enhanced accumulation of VCR in P388/VCR cells by quinidine. The increase of cellular accumulation of VCR was partly explained by inhibition of efflux of VCR and daunomycin from the resistant tumor cells. The mechanism of this phenomenon is discussed in relation to previous findings on calcium channel blockers.
In the pre-clinical study of anticancer candidate compounds, the following three points should be carefully evaluated before decision to enter the clinical trials. Namely, 1) the data on the antitumor efficacies (in vitro and in vivo), 2) animal toxicities and 3) pharmacological studies. Since more attention has been placed on the clinical trials to protect the right of cancer patients, the toxicity data are especially examined carefully using small and large experimental animals. Feasibility to enter in the clinical studies should be examined by above three points in the preclinical studies.
Intraperitoneal inoculation of either levamisole or 2 x 10(6) cells of concanavalin-A (Con-A)-bound L1210 leukemia vaccine produced no cured mice after subsequent ip inoculation of 10(3) live L1210 cells. Combined inocluation of levamisole and Con-A-bound vaccine produced about 20% cure incidence but no prolongation of life span of tumor-bearing mice after inoculation of live L1210 cells. Combined inoculation of levamisole and Con A-free vaccine did not induce detectable immune resistance in mice. These results suggest that levamisole enhanced host response to cell-bound Con-A associated with immunogenic potency of the vaccine. Levamisole given intravenously and orally was as effective as that inoculated intraperitoneally in enhancing the induction of resistance in mice by Con-A-bound vaccine. Dose of levamisole was very critical for this enhancement, being effective at 0.38 mg/kg but not either at 0.75 or 0.19 mg/kg. Furthermore, levamisole restored immune resistance induced by a larger inoculum of Con-A-bound vaccine cells (10(7)) and impaired by cyclophosphamide.
The bis-derivatives (4-6) of 8-hydroxyquinoline, which, like tropolones, readily form a chelate, were synthesized and found to be actively antitumorous in tests of survival using P388 mice. 4 was almost as potent as bistropolone (2a).
The mechanisms of action of a novel macromolecular antitumor antibiotic (SN-07) were examined using cultured mouse lymphoid leukemia L1210 cells. A shoulder exponential-type cytotoxicity was observed when the cells were treated with 3.13 to 100 ng/ml SN-07 for 1 hr and surviving colonies were counted after a 14-day incubation. It was found that 500 ng/ml SN-07 inhibited both RNA and DNA syntheses significantly at 40 and 80 min, respectively, while 8,000 ng/ml did not affect protein synthesis at 80 min. Treatment with a low concentration (80 ng/ml) of SN-07 for 1 hr inhibited both RNA and DNA syntheses after a 24-hr post-incubation. The alkaline elution technique revealed that 8,000 ng/ml SN-07 induced DNA interstrand cross-links time-dependently for 1 to 4 hr, and a 1-hr treatment with 80 to 8,000 ng/ml SN-07 induced DNA breaks after a 24-hr post-incubation. According to flow cytometric analysis, most L1210 cells progressed to the G2 phase in the cell cycle at a cytostatic concentration (25 ng/ml) of SN-07, and typical inhibition of the cell cycle progression was observed at a cytocidal concentration (200 ng/ml).
