Teratogenic effects of the anticonvulsant drugs valproic acid (VPA) and diphenylhydantoin (DPH) on the development of mouse embryos during early organogenesis were studied using the whole embryo culture technique. Embryos with one to seven somites were exposed in vitro to 50-375 micrograms/ml VPA or 15-135 micrograms/ml DPH for up to 42 hours and compared to control embryos cultured in 80% rat serum without either drug. For both VPA- and DPH-treated embryos, a dose-dependent increase in the frequency of abnormal embryos and a decrease in viability were found. VPA and DPH produced a similar pattern of defects. Drug-induced anomalies included open neural tubes in the cranial regions, abnormal body curvature, craniofacial deformities, and yolk sac defects. Ultrastructural changes were noted in the neuroepithelium of exencephalic VPA-treated embryos. Growth and development were retarded in embryos exposed to greater than 35 micrograms/ml DPH or greater than 50 micrograms/ml VPA as indicated by the decrease in protein and DNA content and the reduction in somite number, crown-rump length, and yolk sac diameter. On a molar basis DPH was potentially more teratogenic than VPA, which correlates with the higher lipid solubility of DPH. With VPA, susceptibility to the drug depended on the developmental stage; e.g., at 150 micrograms/ml VPA the frequency of malformations was 70% in embryos with one to four somites as compared to 35% in embryos with five to seven somites.
Seventy-one consecutive patients with small cell lung cancer (SCLC) were treated in the Radiation Oncology Branch of the National Cancer Institute using six different radiation regimens in combination with cyclophosphamide, vincristine and doxorubicin chemotherapy. Patients treated with concurrent chemotherapy-irradiation (CT-RT) experienced better local tumor control than patients treated with sequential CT-RT. Maximum survival with minimum toxicity occurred in the group given a three-week course of concurrent CT-RT. Although concurrent therapy appeared more toxic than sequential therapy, it also appeared to result in more effective tumor control. Precise details of the timing of CT and RT represent important variables in study design of combined modality therapy for SCLC. Carefully controlled clinical trials should be undertaken to define the optimal timing and sequencing of CT-RT, as well as the optimal dose of RT.
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