21312 Pyrimidinederived antimetabolites pyrimidine antagonists

The pyrimidine antagonist cytarabine (also called cytosine arabinoside or Ara C) inhibits synthesis of DNA as well as RNA by displacement

2.13.12 Pyrimidire-derived antimetabolites

of cytosine, from which it differs by its sugar component, arabinose. There have been 11 published reports on pregnancies following cytarabine exposure in the first trimester. Six children were healthy (Aviles 1991, 1990), and one spontaneous miscarriage occurred 20 days after the end of cytotoxic therapy (Zuazu 1991). There were two induced abortions, one of which was induced after 20 weeks with an apparently normally developed fetus (Zemlickis 1992, Lilleyman 1977). Three children had limb anomalies; one of them also had bilateral microtia and atresia of the exterior auditory canal (Wagner 1980). The mother had received cytarabine three times in connection with maintenance therapy for acute lymphatic leukemia: at the time of conception, in week 6/7, and in week 10. This is the only case report of a mono-drug therapy; all the other cases received multi-agent chemotherapy. The second anomalous child had radial aplasia on both sides and four fingers on each hand, with a hypoplastic thumb, a severe brachycephaly, hypoplasia of the basal skull and mid-face, as well as synostosis of the cranial sutures. The mother had been treated with cytarabine and other drugs at the time of conception and thereafter from day 35 or 37 onwards for acute myelocytic leukemia (Artlich 1994). The third case (Schafer 1981) is described above under thioguanine (see section 2.13.11). Regarding the specificity of the teratogenic damage caused by cytarabine, the reader is referred to Vaux (2003), who proposes an embryopathy induced by cyclophos-phamide-methotrexatc-cytarabinc drugs (see section 2.13.6).

We have found approximately 30 published cases of exposure to cytarabine during the second/third trimester; further cases are mentioned in review articles. A large proportion of the children were healthy (Peres 2001, Veneri 1996, Requena 1995, Aviles 1991, 1990, Blatt 1980). There are also reports about late abortions and stillbirths (Greenlund 2001, citations in Zuazu 1991), and, furthermore, of three premature babies with severe but reversible pancytopenia (Hsu 1995, Murray 1994, Engert 1990). Reynoso (1987) reported on three healthy infants (one was premature at 34 weeks' gestation, the second had transient changes in the blood count, the third was a full-term baby) and one premature baby born at 29 weeks' gestation whose mother had received treatment for acute myeloid leukemia (AML) from week 25 of pregnancy onwards. At the age of 2 years, ophthalmologic evaluation revealed congenital adherence of the iris to the cornea of the left eye. Otherwise, the boy was still apparently developing normally at the age of 3 years.

5-Fluomuracil (5-FU) also interferes with DNA and RNA synthesis by displacing uracil. Five healthy children have been reported following local vaginal application of 5-fluorouracil during the first trimester (Kopelman 1990, Odom 1990). Case reports about treatment during the first trimester in conjunction with other therapeutic drugs describe four healthy children (Andreadis 2004, Peres 2001,

Zemlickis 1992), two spontaneous abortions (Giacalone 1999), and a complex deformity after exposure in weeks 11 and 12 (Stephens 1980). Paskulin (2005) describes a child who had been exposed in utero until week 16 to cyclophosphamide, fluorouracil, and doxorubicin, and who was born showing growth restriction, facial dys-morphism, and different malformations of the distal extremities. These anomalies were probably due to cyclophospamide.

The majority of more than 100 children with intrauterine exposure to 5 FU during the second and third trimesters were healthy (Ginopoulos 2004, Berry 1999). Intrauterine growth restriction was reported (Hahn 2006, Zemlickis 1992). Dreicer (1991) describes a boy who had been exposed to high doses of 5-FU during the second/third trimester (20 g in total), was born in week 38 of prcgnancy weighing below average (2660 g); he was normally developed when 2 years old. Concerning the topical application of fluorouracil, refer to Chapter 2,17,

Regarding gemcitabin and capecitabin, there is no information available regarding drug tolerance during pregnancy.

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