Charles University in Prague Faculty of Medicine in Hradec Králové Department of Medical Biochemistry Šimkova 870, P.O. Box 38 500 38 Hradec Králové, Czech Republic E-mail: niang@lfhk.cuni.cz Phone: 00420 49 5816 452 Fax: 00420 495 512 715
Abstract: Numerous papers dealing with chemotherapy management of neoplastic diseases have reported mitoxantrone (MX) â a synthetic aminoanthraquinone, with intercalating properties, to be an important modern therapeutic both in studies involving mice and also humans. Reported adverse effects - nausea, vomiting, myelotoxicity, anemia, cardiotoxicity and immunosuppression - are usually mild or moderate in comparison to other drugs of the same group. For MX, as with many other chemotherapeutic regimens, there is also a relationship between the dose of the drug and its pharmacological response. Higher doses kill greater numbers of tumour cells, though as drug doses are increased, toxicity to normal tissue also increases. The clinical management of toxic side effects would have a great impact in the therapy of the disease. L-carnitine, a vitamin-like substance known to have both hepatoprotective and cardioprotective effects, could be a good candidate to modulate the toxicity profile of MX. This present study investigates the therapeutic effect of MX in combination with L-carnitine (LCAR) on the growth of a solid form of Ehrlich tumour inoculated into mice. LCAR was administered subcutaneously at doses of either 200 or 100 mg kgâ1 on day 6 and 13 after tumour inoculation, 1 h prior to the treatment with MX. Mitoxantrone was administered intravenously at doses of 3 or 6 mg kgâ1. We found that LCAR had no potentiating effect on the efficacy of MX, in terms of either slowing tumour growth or increasing the survival of mice. Nevertheless, therapeutic effects can be assumed at higher doses of both drugs based on values calculated from an index of relative hazards.
Key Words: Mitoxantrone; L-Carnitine; Ehrlich tumour; Index of relative hazards
Acknowledgment: This work was supported by Ministry of Education of the Czech Republic Research Project MSM0021620820.
Abstract: Disease progression during intensive chemotherapy of cancers is the early manifestation of the tumor resistance to chemotherapeutic agents. The use of resistance modulating agent may offer an opportunity to prevent the development of the disease. Recent studies have shown that 2-deoxy-D-glucose (2-DG), an inhibitor of glycolytic ATP production significantly enhances the cytotoxic effects of anticancer drugs like alkylating agents. Since tumor cells preferentially use anaerobic glycolysis to cover their energy needs, we hypothesized that combination of 2-DG and DNA damage causing cytotoxic agents such as mitoxantrone could be useful in controlling the tumor progression. In the studies reported here, we evaluated the cytotoxic activity of MX-2-DG combination effect on DNA and protein synthesis of a resistant mouse leukemia L1210 cell line during a short term culture. The biosynthesis of macromolecules was measured by determining the incorporation rate (IR) of [6-3H] thymidine and uniformly labeled [U-14C] amino-acid mixture into acid-insoluble fraction of leukemia cells. The inhibitory concentration (IC50) was determined for 2-DG alone and its combination with MX. 2-DG was active in inhibiting both nucleic acid and protein biosynthesis in cultured L1210 resistant tumor cells. IC50 values of 2-DG alone for incorporation of [6-3H] thymidine and uniformly labeled [U-14C] amino acid mixture were 9.6 mmol.l-1 in DNA synthesis and 10.5 mmol.l-1 in protein synthesis. In combination with MX, the IC50 values were 13.6 and 44.1 mmol.l-1 for DNA and protein biosynthesis, respectively. No synergism was observed.
Key Words: Mitoxantrone, 2-deoxy-D-glucose, DNA and protein synthesis, mouse leukemia L1210 cells resistant to mitoxantrone
Abstract: We have commenced a series of experiments to evaluate the effect of carnitine derivatives on the antineoplastic activity of mitoxantrone (MX) on various animal cancers. This report describes the therapeutic effect of MX in combination with L-carnitine (LCAR) on the growth of a solid form of Ehrlich tumor (STE) inoculated into mice. LCAR was administered subcutaneously at doses of either 200 or 100 mg/kg on days 6 and 13 after tumor inoculation, one hour prior the treatment with MX. Mitoxantrone was administered intravenously at doses of 3 or 6 mg/kg. We found that LCAR had no potentiating effect on the efficacy of MX, in terms of either slowing tumor growth or increasing the survival of mice. Nevertheless, therapeutic effects can be assumed at higher doses of both drugs based on values calculated from an index of relative hazards.
Key Words: Mitoxantrone, L-carnitine, Ehrlich tumor, index of relative hazards
Acknowledgment: This work was supported by Ministry of Education of the Czech Republic Research Project MSM0021620820.
