Mitoxantrone

Bisantrene (56), also known as orange crush", is a broad spectrum intercalating antitumor agent competing with doxorubicin and the somewhat more closely related quinone mitoxantrone (51)... 

P-gp (ABCB1) Verapamil, digoxin, mitoxantrone, vinblastine, doxorubicin, losartan, talinolol, cortisol, dexamethasone, colchicine, loperamide, domperidone, indinavir, erythromycin, tetracycline, itraconazole, cyclosporine, methotrexate, amitryptyline, phenobarbital, morphine, cimetidine, and others... 

BCRP (ABCG2) Cisplatin, folate, methotrexate, mitoxantrone, topotecan, irinotecan, steroids (cholesterol, testosterone, progesterone), certain chlorophyll metabolites, and others... 

In general, the mechanisms of action are not cell cycle specific, although some members of the class show greatest activity at certain phases of the cell cycle, such as S-phase (anthracyclins, mitoxantrone), Gl- and early S-phases (mitomycin C) and G2- and M-phases (bleomycins). 

Plasma digoxin levels may decrease when the drug is administered with bleomycin. When bleomycin is used witii cisplatin, there is an increased risk of bleomycin toxicity Pulmonary toxicity may occur when bleomycin is administered with other antineoplastic drugs. Plicamycin, mitomycin, mitoxantrone, and dactino-mycin have an additive bone marrow depressant effect when administered with other antineoplastic drugs. In addition, mitomycin, mitoxantrone, and dactinomycin decrease antibody response to live virus vaccines. Dactinomycin potentiates or reactivates skin or gastrointestinal reactions of radiation therapy There is an increased risk of bleeding when plicamycin is administered witii aspirin, warfarin, heparin, and the NSAIDs. 

C47H7,NOis 55881-06-6) see Midecamycin acetate Ieuco-l,4,S,8-tetrahydroxyanthraquinone (C 4HsOfi 81-60-7) see Mitoxantrone levonorgestrel acetate (C2,H i07 13732-69-9) see Norgestimate levulinic acid... 

Limtraknl, P. et al.. Modulation of the function of three ABC drug transporters, P-glycoprotein (ABCBl), mitoxantrone resistance protein (ABCG2) and multidrug resistance protein 1 (ABCCl) by tetrahydroenrenmin, a major metabolite of cur-enmin. Mol. Cell Biochem., 296, 85, 2007. 

Mitoxantrone should be reserved for patients with rapidly advancing disease who have failed other therapies. 

Mitoxantrone (Novantrone) 12 mg/m2 up to 140 mg/m2 IV Every 3 months Nausea 76% Alopecia 61 % Menstrual disorders 61% Urinary tract infection 32% Amenorrhea 25% Leukopenia 1 9% y-Glutamyl transpeptidase increase 1 5%... 

Pharmacology and Mechanism of Action Mitoxantrone is an anthracenedione antineoplastic that is indicated for multiple sclerosis. The mechanisms of action thought to be important for MS are as follows ... 

Adverse Effects Adverse effects are seen regularly in patients given mitoxantrone (see Table 26-3). Patients often experience bluish discoloration of the sclera and the urine for 24 hours after infusion.46 Transient leukopenia and neutropenia are common with a nadir 10 to 14 days after the infusion. Patients should avoid exposure to infectious individuals during this time.46 Patients taking mitoxantrone should not receive live virus vaccines other vaccines should be held for 4 to 6 weeks after a mitoxantrone dose.46 Amenorrhea, caused by a direct toxic effect on the ovary, may be permanent, an important consideration because the MS population includes women of childbearing potential.27... 

Cardiotoxicity is a serious, rare adverse effect of mitox-antrone. The incidence of congestive heart failure was 0.15% in patients with normal left ventricular ejection fraction and 2.18% in those who had asymptomatic left ventricular ejection fraction of less than 50% at baseline.46 Therefore, mitoxantrone should not be used in patients with baseline cardiomyopathy, even if asymptomatic. The risk of cardiotoxicity is dose-related. The maximum lifetime dose of mitoxantrone is 140 mg/m2, or about 3 years of MS therapy. The use of cyclooxygenase-2 inhibitors should be avoided in patients receiving mitoxantrone because of a potential for worsening cardiac toxicity.46... 

Acute myelogenous leukemia has been observed in 0.07% of MS patients treated with mitoxantrone.46 This form of acute leukemia appears within 2 to 4 years of initiating mitoxantrone and is generally responsive to standard antileukemic therapy. 

Dosing and Administration Mitoxantrone is infused intravenously over 30 minutes to reduce the chance of cardiotoxicity.46 Mitoxantrone is administered every 3 months, if cardiac function and laboratory values are normal (Table 26-6). 

Mitoxantrone Complete blood count, bilirubin, Before each infusion... 

This royal-blue-colored drug is an anthracenedione that inhibits DNA topoisomerase II. The pharmacokinetics of mitoxantrone may best be described by a three-compartment model, with an a half-life of 3 to 10 minutes, a 3 half life of 0.3 to 3 hours, and a median terminal half-life of 12 days. Biliary elimination appears to be the primary route of elimination, with less than 10% of the drug eliminated by the kidney.23 Mitoxantrone has shown clinical activity in the treatment of acute leukemias, breast and prostate cancer, and non-Hodgkin s lymphomas. Myelosuppression, mucositis, nausea and vomiting, and cardiac toxicity are side effects of this drug. The total cumulative dose limit is 160 mg/m2 for patients who have not received prior anthracycline or mediastinal radiation. Patients who have received prior doxorubicin or daunorubicin therapy should not receive a cumulative dose greater than 120 mg/m2 of mitoxantrone. Patients should be counseled that their urine will turn a blue-green color. 

Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. New Engl J Med. 2004 351(15) 1502—1512. 

In regard to the antineoplastic potentials of Rubiaceae, some evidence has already been presented that clearly demonstrates that anthraquinones inhibit the enzymatic activity of topoisomerase II. An example of antineoplastic anthraquinones that target topoisomerase II is mitoxantrone (Novatrone ), which is currently approved for clinical use in the United States (16). In the Pacific Rim, about 150 species of plants classified within the family Rubiaceae are medicinal, of which Prismatomeris albidiflora, Krtoxia valeriartoides, Damnacanthus indicus, and Morinda umbellata are known to produce anthraquinones. An interesting development from Rubiaceae would be to investigate its members for anthraquinones and assess them for topoisomerase inhibitors. The discovery of inhibitors of topoisomerase II of clinical antineoplastic value can be reasonably expected. 

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