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Comparative in vitro toxicity of mitoxantrone and adriamycin in human granulocyte-macrophage progenitor cells
Abstract:
Mitoxantrone (MIT) has recently been introduced into cancer therapy as a possible substitute for the structurally related drug, adriamycin (ADR), because it causes less cardiotoxicity and fewer gastrointestinal side effects. However, the dose-limiting toxicity of MIT is pronounced neutropenia. The in vitro hematoxicity of both drugs in granulocyte-macrophage precursor cells (GM-CFCs) was analyzed using drug-exposure schedules analogous to the principles of the in vivo pharmacokinetics of MIT. Bone-marrow and peripheral-blood cells were exposed to 0.075-20 ng/ml MIT or ADR for 5, 20, 60, and 120 min, and for 14 days. The 14-day exposure resulted in Do values of 0.95 and 0.68 ng/ml for bone-marrow and peripheral-blood GM-CFCs subjected to MIT. Exposure to ADR resulted in Do values of 5.43 and 5.13 ng/ml, respectively. As was the case after 14-day exposure to MIT or ADR, short-term exposure again revealed that peripheral-blood GM-CFCs were more sensitive to both drugs. Moreover, at low concentrations, ADR was less toxic than MIT in both types of GM-CFCs, but was more toxic than MIT when a concentration of 20 ng/ml was used. The intracellular concentration of MIT, as measured by high-performance liquid chromatography, was constantly below 1 ng per 2 X 10(7) cells, even when it was applied at a concentration of 20 ng/ml for an exposure time of 2 h. The fact that such low concentrations of MIT are toxic for hemopoietic precursor cells may explain the myelotoxicity of this drug. However, the difference between the precursor-cell toxicity of MIT and that of ADR was small when their respective therapeutic doses were taken into consideration. Further analyses of their toxicity in stem cells and/or the microenvironment would appear to be needed.
Insights
Mitoxantrone (MIT) and adriamycin (ADR) exhibit hematotoxicity, with MIT causing significant neutropenia. Peripheral blood cells are more sensitive to both drugs, and MIT
Area of Science:
- Hematology
- Pharmacology
- Cancer Therapeutics
Background:
- Mitoxantrone (MIT) is a cancer therapeutic alternative to adriamycin (ADR) due to reduced cardiotoxicity and gastrointestinal side effects.
- However, MIT's dose-limiting toxicity is severe neutropenia.
- Understanding MIT's hematotoxicity is crucial for its clinical application.
Purpose of the Study:
- To compare the in vitro hematotoxicity of Mitoxantrone (MIT) and adriamycin (ADR) on hematopoietic precursor cells.
- To analyze drug-exposure schedules analogous to in vivo pharmacokinetics.
- To investigate the sensitivity of bone-marrow and peripheral-blood granulocyte-macrophage colony-forming cells (GM-CFCs) to MIT and ADR.
Main Methods:
- In vitro exposure of bone-marrow and peripheral-blood cells to varying concentrations of MIT and ADR (0.075–20 ng/ml).
- Short-term (5–120 min) and long-term (14 days) drug exposure schedules.
- Analysis of drug toxicity using Do values and intracellular concentration measurements via high-performance liquid chromatography.
Main Results:
- Long-term exposure showed MIT was more toxic to GM-CFCs (Do values 0.95–0.68 ng/ml) than ADR (Do values 5.43–5.13 ng/ml).
- Peripheral-blood GM-CFCs were consistently more sensitive to both drugs than bone-marrow GM-CFCs.
- At low concentrations, ADR was less toxic than MIT, but at 20 ng/ml, ADR became more toxic.
Conclusions:
- Low intracellular concentrations of MIT are toxic to hemopoietic precursor cells, potentially explaining its myelotoxicity.
- The difference in precursor-cell toxicity between MIT and ADR is small relative to their therapeutic doses.
- Further research into stem cell and microenvironment toxicity is warranted.