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Neurosurgery:
Experimental Study

The Antitumor Effect of MX2, a New Morpholino Anthracycline, against Malignant Glioma Cell Lines and Its Subcellular Distribution

Kabuto, Masanori M.D.; Kubota, Toshihiko M.D.; Kobayashi, Hidenori M.D.; Nakagawa, Takao M.D.; Kitai, Ryuhei M.D.

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Abstract

THE CHEMOTHERAPEUTIC EFFECT of MX2 (3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin), a new lipophilic morpholino anthracycline, against rat C6 and human T98G glioma cells, was examined in vitro and in vivo. The subcellular distribution of MX2 was also studied. The drug concentrations of MX2 required for the 50% inhibition of cell growth (IC50) for C6 and T98G cells were 25.5 ± 1.3 ng/ml and 70.6 ± 6.8 ng/ml, respectively, which were much lower than the IC50 values for nimustine (ACNU). A C6 subline resistant to ACNU, C6/ACNU, was established by continuous exposure to graded concentrations of ACNU. The IC50 of MX2 for C6/ACNU was 28.3 ± 2.2 ng/ml, indicating no cross-resistance to MX2. In the rats bearing the intracerebral C6 tumors, the life span was increased by about 40 to 100% after intravenous administration of MX2 at doses ranging from 1 to 3 mg/kg of body weight. Confocal laser scanning microscopy demonstrated visually the good accumulation of MX2 in the implanted intracerebral C6 tumors, as well as its predominant distribution in the cytoplasm over the nucleus in both cell lines in vitro. Ultrastructural studies also demonstrated the cytotoxic effects of MX2 against glioma cells. Our results suggest that MX2 may be a useful chemotherapeutic agent in the treatment of malignant gliomas and that confocal laser scanning microscopy is useful for the study of the cellular pharmacokinetics of anthracycline derivatives, such as MX2.

Copyright © by the Congress of Neurological Surgeons

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