thioguanine-anhydrous and Abnormalities--Drug-Induced

Topics: Abnormalities, Drug-Induced; Adult; Aged; Azathioprine; Bone Marrow Diseases; Chemical and Drug Induced Liver Injury; Child; Cost-Benefit Analysis; Drug Administration Schedule; Drug Approval; Drug Costs; Drug Hypersensitivity; Drug Interactions; Female; Genetic Testing; Humans; Immunosuppressive Agents; Infections; Kidney Diseases; Lactation; Male; Methyltransferases; Nausea; Neoplasms; Off-Label Use; Patient Education as Topic; Pregnancy; Risk Factors; Skin Diseases; Thioguanine; Virus Diseases

Hydroxyurea (HU) and 6-mercaptopurine riboside (6-MPr) are used as cytostatic chemotherapeutics. Their teratogenic potential in experimental animals has been well known for several decades. Generally, it is assumed that the toxicity of both agents is due to an interference with enzymes of DNA synthesis. In the case of 6-MPr, it was speculated that the teratogenicity in rodents might be paralleled by or even correlated to an incorporation of 6-thioguanine into the DNA of the embryos. In this study, the interaction between these two compounds with regard to teratogenicity in NMRI mice was investigated. Dose-response data of 6-MPr (s.c.-treatment) were published earlier. First, a dose-response study with HU alone (i.p.-treatment) was performed. From these data, the doses for the combination study were derived: HU 250 mg/kg (NOAEL dose) and 6-MPr 16 mg/kg (strongly teratogenic dose). In all experimental groups the substances were administered to the dams once on day 11 of gestation. Combination effects were investigated applying various dosing regimens. In group I treatment was simultaneous, in group II HU was administered 2 h before 6-MPr, in group III 2 h after 6-MPr. The differences in the overall frequency of gross structural abnormalities were moderate. However, when analysing the effects in more detail (single abnormalities), group III exhibited great differences: 1) 6-MPr co-treatment increased the frequency of HU effects (skull defects) and 2) HU co-treatment decreased the frequency of 6-MPr effects (limb defects) when compared to the findings of the dose-response studies. In addition, the influence of HU on the 6-MPr-induced DNA modification was determined by measuring the incorporation of 6-thioguanine into the DNA of day-11 embryos. As expected, the HU co-treatment corresponding to the group III dosing regimen of the teratogenicity experiment decreased the incorporation rate by ca. 40%. This was in parallel to the decrease in the frequency of 6-MPr effects in the teratogenicity III group. This finding may be considered as a further indication that in the case of 6-MPr, DNA modification is accompanying teratogenicity.

Topics: Abnormalities, Drug-Induced; Animals; DNA; Dose-Response Relationship, Drug; Female; Hydroxyurea; Limb Deformities, Congenital; Maternal-Fetal Exchange; Mice; Pregnancy; Skull; Teratogens; Thioguanine; Thioinosine

The coexistence of leukemia and pregnancy is extremely rare. This paper describes two cases of acute promyelocytic leukemia diagnosed during the second trimester of pregnancy and the most suitable approach to the management of this situation is analyzed. Possible teratogenic effects of mono- or polychemotherapy during pregnancy, depending upon the gestational age at which chemotherapy is given, are discussed.

Topics: Abnormalities, Drug-Induced; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Cytarabine; Daunorubicin; Etoposide; Fatal Outcome; Female; Humans; Leukemia, Promyelocytic, Acute; Mitoxantrone; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Recurrence; Thioguanine

Experience with the use of cytotoxic drugs in the first trimester of pregnancy is limited. We report on the clinical phenotype and infantile development of a girl born to a 36-year-old mother. Before recognition of pregnancy, the latter had been treated for acute myelocytic leukaemia receiving cytarabine, daunorubicin and doxorubicin at conception and cytarabine and thioguanine at about 35-37 days post conception. At delivery, there were severe brachycephaly, hypoplasia of the anterior cranial base and the midface as well as synostoses of both coronal and metopic sutures. Further findings included bilateral four-finger hands with hypoplastic thumbs and absent radii. This phenotype is reminiscent of the Baller-Gerold syndrome. The child, at present 15 months old, has had to undergo two operations for fronto-orbital advancement because of insufficient growth of the mid-face, nasal airway hypoplasia and increased intracranial pressure. Motor milestones are slightly retarded--neurodevelopment is otherwise normal. These findings are discussed in the context of the few previous reports and are particularly important for future genetic counselling.

Topics: Abnormalities, Drug-Induced; Adult; Antineoplastic Combined Chemotherapy Protocols; Arm; Craniosynostoses; Cytarabine; Daunorubicin; Doxorubicin; Female; Humans; Infant, Newborn; Leukemia, Myeloid, Acute; Phenotype; Pregnancy; Pregnancy Complications, Neoplastic; Thioguanine

The clinical teratogenicity of the new antileukemic chemotherapeutic agents administered to mothers early in the first trimester of pregnancy is not well defined. Cytarabine and thioguanine were given in identical doses to the same mother during the first trimester of two separate pregnancies. Both pregnancies resulted in viable babies, one with and one without congenital malformations. This case illustrates the highly unpredictable clinical effects on the fetus of chemotherapy early in pregnancy.

Topics: Abnormalities, Drug-Induced; Adult; Antineoplastic Agents; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Infant, Newborn; Leukemia; Male; Pregnancy; Pregnancy Complications; Thioguanine; Thumb; Toes

Topics: Abnormalities, Drug-Induced; Abortion, Therapeutic; Adult; Chromosome Aberrations; Chromosome Disorders; Chromosomes, Human, 6-12 and X; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Mosaicism; Pregnancy; Pregnancy Complications, Hematologic; Thioguanine; Trisomy

Topics: Abnormalities, Drug-Induced; Adenine; Female; Mercaptopurine; Neoplasms; Neoplasms, Experimental; Pharmacology; Placenta; Pregnancy; Purines; Pyrazoles; Pyrimidines; Rats; Research; Teratogenesis; Thioguanine; Toxicology