Cancer in Pregnancy: Mitoxantrone

Mitoxantrone (Novantrone) is 1,4-dihydroxy-5,8-bis ((2-((2-hydroxyethyl)amino)ethyl)amino)anthraquinone, often abbreviated DHAQ. It is an antineoplastic agent that appears to bind DNA and produce strand scission ^1,2.

	Setting	Treatment	Outcomes
In vitro studies	mammalian assay systems		Mitoxantrone is genotoxic in several mammalian assay systems ^3-5.
	Species studied
Animal studies *	Rabbits	up to 0.4 mg/kg/day	We have been unable to locate references on possible developmental toxicity of mitoxantrone; however, ametantrone, a similar agent, was teratogenic in rabbits at doses of 0.4mg/kg/day but not at 0.2 mg/kg/day ⁶.
	Rats	up to 6 mg/kg/day	Ametantrone was not teratogenic in rats at up to 6 mg/kg/day ⁶.
	Study design
Human studies	Case reports	2nd trimester Combination with: cytarabine + idarubicin	Two case reports have described the use of mitroxantrone during the second trimester of human pregnancy ^7,8. In one case, five weeks of therapy with mitroxantrone and cytarabine up to developmental week 28 were accompanied by normal fetal growth ⁷. Subsequent introduction of idarubicin to replace mitroxantrone was followed by death of the fetus. In the second case, a mother treated with a variety of chemotherapeutic agents including mitroxantrone from 24 to 34 weeks of gestation delivered a normal female infant ⁸.
Breast feeding	Pharmacokinetic		Mitoxantrone is excreted in breast milk in small amounts ⁸.
	Case reports		Based on data from one lactating mother, this agent is apparently stored and released slowly into breast milk for at least one month after its administration ⁸. Although the quantities of drug in milk were very low (10-20 ng/mL), breastfeeding was not recommended in this case.

* - None of the animal studies reported in this table were conducted at The Hospital for Sick Children, Toronto, or by Motherisk.

References

Alberts DS et al: Pharmacology of mitoxantrone: mode of action and pharmacokinetics. Invest New Drugs 3:101-7, 1985.
Locher SE, Meyn RE: Relationship between cytotoxicity and DNA damage in mammalian cells treated with anthracenedione derivatives. Chem Biol Interact 46:369-79, 1983.
Manandhar M et al: Genetic toxicology profile of the new antineoplastic drug mitoxantrone in the mammalian test systems. Arzneimittelforschung 36:1375-9, 1986.
Au WW et al: Comparative structure-genotoxicity study of three aminoathraquinone drugs and doxorubicin. Cancer Res 41:376-9, 1981.
Rosenberg LJ, Hittelman WN: Direct and indirect clastogenic activity of anthracenedione in Chinese hamster ovary cells. Cancer Res 43:3270-5,1983.
Petrere JA et al: Teratology studies of ametantrone acetate in rats and rabbits. Teratology 34:271-8, 1986.
Reynoso EE, Huerta F: Acute leukemia and pregnancy - fatal fetal outcome after exposure to idarubicin during the second trimester. ActaOncologica 33:703-16, 1994.
Azuno Y, Kaku K, Fujita N: Mitoxantrone and etoposide in breast milk. Am J Hematol 48:131-2, 1995.

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