Quinacrine enhances carmustine therapy of experimental rat glioma.

OBJECTIVE: The high rate of mutagenesis in malignant cells has been considered to be a primary factor in the appearance of chemotherapy-resistant cell clones in glioblastomas. Quinacrine binds strongly to deoxyribonucleic acid, preventing mutagenesis. We investigated whether quinacrine could improve carmustine therapy in C6 cell cultures and in C6 malignant gliomas implanted subcutaneously into Wistar rats. METHODS: A potential chemopreventive effect of quinacrine on acquired resistance to carmustine therapy was studied in vitro and in vivo. Deoxyribonucleic acid damage was measured in cultured C6 cells by using the micronucleus test. Wistar rats with subcutaneously implanted C6 gliomas were treated with carmustine, quinacrine, or carmustine plus quinacrine, using pharmacological schemes similar to those used for human patients. RESULTS: The addition of quinacrine to cultured C6 cells did not modify carmustine-induced cytotoxicity; however, the deoxyribonucleic acid damage in surviving cells was minor, as indicated by the frequency of micronucleated cells. The surviving cells continued to be susceptible to a second exposure to carmustine, in contrast to non-quinacrine-treated control cells, which developed resistance to carmustine in a subsequent exposure (P < 0.05). The rate of tumor remission was higher for glioma-bearing rats treated with quinacrine plus carmustine, compared with rats treated with carmustine alone (P < 0.01). CONCLUSION: The addition of quinacrine to carmustine therapy increases the antineoplastic effect of the carmustine therapy. Our results suggest that chemical inhibition of mutagenesis in malignant glial cells during chemotherapy prevents the appearance of resistant clones.

Genotoxic activity of praziquantel.

Praziquantel is a synthetic drug with a remarkable activity against parasites, particularly treamatodes and cestodes. Initial genotoxicity tests used a spectrum of endpoints including tests in bacteria, yeasts, mammalian cells and Drosophila and each one gave negative results. Effects on reproductive cells of mice were negative as well. However, host mediated studies in mice and humans were contradictory and a comutagenic effect with several mutagens and carcinogens was found. Later studies, including monitoring in humans and pigs have shown that Praziquantel induces a greater frequency of hyperploid lymphocytes as well as structural chromosomal aberrations, but not in all the individuals treated. In vitro studies have demonstrated that Praziquantel can induce micronuclei in syrian hamster embryonic (SHE) cells and in lymphocytes of some individuals. The same was found about structural chromosomal aberrations. Fetal death and fetal resorption were found when Praziquantel was administered in high doses to pregnant rats between the 6th and 10th day of gestation. Due to its efficiency as a parasiticide, Praziquantel is in use in Latin-American, Asiatic, African and East-European countries where infections by trematodes and cestodes are frequent. However, the extensive use of Praziquantel in multiple reinfections, in non-infected and non-diagnosed individuals for prevention, in higher doses or repeated doses for cysticercosis treatment and in individuals exposed to environmental mutagens, in conjunction with new findings about its metabolism and genotoxic properties, make it necessary to further evaluate the potential of this drug not only to be mutagenic per se, but to contribute in the development of neoplasm.

Methods for the analysis of cellular kinetics in PHA-stimulated blood lymphocytes using BrdU incorporation. A comparative study.

The cellular cycle (cc) span was measured by using differential sister-chromatid staining (DSCS) and applying the following methods: cellular cycle time (cct) according to the graphic method of Dutrillaux and Fosse (G-cct); the analytical equation (A-cct) proposed in the present paper, and the average generation time (AGT) suggested by Ivett and Tice. The mean values obtained by the three methods were 12.5, 12.7, and 19.5 h, respectively. A-cct is the more precise method, since the equation of the analytical procedure allows the utilization of numerical data, and when the graphical method is used, the values plotted in a graph may vary according to the employed scale. Cct is the choice over AGT because the first evaluates actively dividing cells and only considers those at M2 or M3. It will be useful to study cell proliferation kinetics in genetic pathological conditions and to investigate with accuracy the effect of cytostatic and cytotoxic drugs.