Preclinical evaluation of 9-chloro-2-methylellipticinium acetate alone and in combination with conventional anticancer drugs for the treatment of human brain tumor xenografts.

Some ellipticine derivative salts, including 9-chloro-2-methylellipticinium (CME), have been found to have a marked selectivity against all eight brain tumor cell lines of the U.S. National Cancer Institute's disease-oriented in vitro screen. We initiated in vivo antitumor studies to explore the feasibility for further development of this class of compounds. We found that CME was extremely toxic to nude mice when given i.p. at a dose of 25 mg/kg for 3 consecutive days. Animals treated by this route experienced an increase in hepatic transaminases and histopathological changes in the liver, compatible with mitochondrial damage. In contrast, when the portal circulation was bypassed and the same dose of CME was given i.v., animals tolerated daily bolus injections for 5 consecutive days. This 5-day i.v. bolus schedule had consistent antitumor activity, with 28.1% growth delay on s.c. implanted human U251 gliomas. When the potentially high peaks of CME in the portal circulation were avoided by using a 3-day continuous infusion with osmotic minipumps implanted i.p. to release 3.4 mg kg(-1) h(-1) or 6.6 mg kg(-1) h(-1) CME, there were only modest increases in liver enzymes and leukopenia, but no meaningful antitumor activity was observed. In contrast, continuous infusion in the s.c. space was well tolerated and was accompanied by a demonstrable growth delay in s.c. U251 human gliomas of 37.8%. When CME was used in conjunction with carmustine, etoposide or cisplatin, no synergistic activities were observed, but additive effects were demonstrated. Our pharmacokinetic and disposition studies with CME argue against the notion that large and invasive tumors in the brain lack blood-brain barrier features. When CME was used in animals bearing orthotopically implanted U251 gliomas in the brain of nude mice, the survival of the treated animals was not better than vehicle controls, and the addition of CME to carmustine therapy did not improve the survival of those animals treated with carmustine alone. We conclude that, in spite of its marked cytotoxicity in vitro on a variety of human brain tumor cell lines, including U251 glioma cells, CME has a modest antitumor effect on extracranially implanted U251 glioma tumors, and no beneficial effect in animals bearing the same U251 tumor in the brain, owing to a poor penetration into the brain parenchyma.

Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppression, and has potent antitumor activity In vivo against human leukemia and lymphoma xenografts.

Flavopiridol is a novel semisynthetic flavone derivative of the alkaloid rohitukine. Flavopiridol is known to inhibit potently the activity of multiple cyclin-dependent kinases. We have assessed its effects on normal and malignant cells in preclinical animal models of localized and disseminated human hematopoietic neoplasms. Flavopiridol, when administered as daily bolus intravenous (IV) injections, produced selective apoptosis of cells in the thymus, spleen, and lymph nodes, resulting in atrophy of these organs. With the exception of the intestinal crypts, apoptosis or tissue damage was absent in all other organs investigated (kidneys, liver, lungs, bone/bone marrow, muscle, and heart). Flavopiridol had a marked apoptotic effect documented by DNA nick-end labeling, or DNA agarose gels in xenografts of human hematopoietic tumors HL-60, SUDHL-4, and Nalm/6. After treatment with 7.5 mg/kg flavopiridol bolus IV or intraperitoneal on each of 5 consecutive days, 11 out of 12 advanced stage subcutaneous (s.c.) human HL-60 xenografts underwent complete regressions, and animals remained disease-free several months after one course of flavopiridol treatment. SUDHL-4 s.c. lymphomas treated with flavopiridol at 7.5 mg/kg bolus IV for 5 days underwent either major (two out of eight mice) or complete (four out of eight mice) regression, with two animals remaining disease-free for more than 60 days. The overall growth delay was 73.2%. The acquired immunodeficiency syndrome-associated lymphoma AS283 showed no significant response when flavopiridol was used in advanced s.c. tumors, but when treatment was initiated in early stages, there was a complete regression of the early tumors, and a significant overall growth delay (>84%). When flavopiridol was used in severe combined immunodeficient mice bearing disseminated human acute lymphoblastic leukemia Nalm/6 cells, there was 15-day prolongation in survival (P = .0089). We conclude that flavopiridol greatly influences apoptosis in both normal and malignant hematopoietic tissues. This activity was manifested in our study as a potent antileukemia or antilymphoma effect in human tumor xenografts, which was dose and schedule dependent. These findings provide compelling evidence for the use of flavopiridol in human hematologic malignancies.