Regulation of angiogenesis and tumorigenesis by signal transduction cascades: lessons from benign and malignant endothelial tumors.

Oncogenes and tumor suppressor genes are implicated in the regulation of the angiogenic switch. Much of the data accumulated to date uses NIH 3T3 cells, which are deficient in the tumor suppressor gene p16, as models for these studies. We have used a novel system, derived by sequential introduction of a temperature-sensitive SV40 large T antigen and oncogenic H-ras, to study the angiogenic switch. The results from our studies differ from those using NIH3T3 cells, but have been confirmed by multiple other groups. The data from all of these studies suggest that there is synergy between inactivation of the p53 tumor suppressor gene and activation of the phosphoinositol-3-kinase pathway (PI-3-K), as well as synergy between inactivation of the p16 tumor suppressor gene and activation of the MAP kinase pathway. These findings suggest that there are predictable behaviors of tumors that may be assessed by the status of p53 or p16 in a biopsy, and that these predictable changes in signal transduction may be useful both prognostically and in the design of rationally based drug therapy of benign and malignant tumors.

Treatment of Diamond-Blackfan anemia with recombinant human interleukin-3.

This report describes the response of eighteen Diamond-Blackfan anemia (DBA) patients to recombinant human interleukin-3 (rhIL-3). rhIL-3 was administered subcutaneously once daily on an escalating dose schedule (0.5 to 10 micrograms/kg/d). The rhIL-3 dose was escalated every 21 days until erythroid response was attained, grade III or IV nonhematologic toxicity was observed, or the maximum rhIL-3 dose was reached. Four patients experienced clinically significant erythroid responses. Two of the responders were steroid-dependent and transfusion-independent, while two were steroid-independent and transfusion-dependent. Baseline clinical or laboratory parameters, in particular in vitro bone marrow erythroid progenitor assays, were not useful in predicting rhIL-3 response. rhIL-3 administered at 5 to 10 micrograms/kg/d was associated with an increase in total white blood cell count, secondary to increases in neutrophils, eosinophils, and lymphocytes. Patients experienced a dose-dependent elevation in absolute eosinophils across the entire dose range. Two of the responding patients remain on maintenance rhIL-3, without diminution of effect at 244 and 370 + days. rhIL-3 was discontinued in the other two responders, because of the development of deep venous thrombi.

Successful treatment of Diamond-Blackfan anemia with interleukin 3.

This report describes the response of 18 Diamond-Blackfan anemia (DBA) patients to recombinant human interleukin 3 (rhIL-3). rhIL-3 was administered s.c. once daily on an escalating dose schedule (0.5-10 micrograms/kg/day). The rhIL-3 dose was escalated every 21 days until erythroid response was attained, grade III or IV nonhematologic toxicity was observed, or the maximal rhIL-3 dose was reached. Four patients experienced clinically significant erythroid responses. Two of the responders were steroid-dependent and transfusion-independent, while two were steroid-independent and transfusion-dependent. Baseline clinical or laboratory parameters, in particular in vitro bone marrow erythroid progenitor assays, were not useful in predicting rhIL-3 response. Two of the responding patients remain on maintenance rhIL-3 without diminution of effect at 490 and 855+ days. rhIL-3 was discontinued in the other two responders because of the development of deep venous thrombi.