Clin Cancer Res
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Gliomas are tumors of the central nervous system that may be inherited in some patients. The gene(s) responsible for the clustering of gliomas in families have not yet been identified. Molecular studies of sporadic high-grade gliomas have revealed mutations or deletions of the genes encoding the protein kinase inhibitors p16(INK4A) and p15(INK4B) in a large proportion of tumors. ⋯ Genomic DNA from index members of these families was screened by PCR-single-strand conformational polymorphism analysis. We did not detect any functional mutations in the p16(INK4A), p15(INK4B), or CDK4 genes, although two individuals did have a previously described A140T polymorphism in p16(INK4A). Thus, despite the association between the sporadic forms of high-grade glioma and abnormalities of p16(INK4A), p15(INK4B), or CDK4, we found no evidence that germ-line mutations in the coding region of these three genes predispose to inherited glial tumors.
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Preclinical and clinical studies have documented the pharmacological interest in camptothecin derivatives in the treatment of resistant tumors. In particular, topotecan, a water-soluble derivative, exhibited promising activity in pretreated ovarian carcinoma. The present study investigated the pattern of tumor response in two human ovarian carcinoma xenografts and in their cisplatin-resistant sublines characterized by different mechanisms of drug resistance. ⋯ The antitumor efficacy of topotecan in the four tumors reflected a different cell response to drug-induced DNA damage, as suggested by different perturbations of cell cycle progression. Indeed, only in the subline refractory to topotecan in vivo, IGROV-1/Pt1, did we observe a persistent arrest of the cells in the S-phase, resulting in a cytostatic and not a cytotoxic effect, since a low level of apoptosis was induced by the drug. In conclusion, the current results support that determination of drug-induced apoptosis is a useful predictor of tumor response to topotecan in ovarian carcinomas and suggest that p53 gene status may be a critical determinant of cell response to topoisomerase inhibitors.
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Vascular endothelial growth factor (VEGF) plays a pivotal role in the development of neovascularization in both physiological and pathological processes, e.g., developmental and reproductive angiogenesis, proliferative retinopathies, and cancers. Several solid tumors produce ample amounts of VEGF, which stimulates proliferation and migration of endothelial cells, thereby inducing neovascularization by a paracrine mechanism. Recently, VEGF expression has been shown to significantly affect the prognosis of different kinds of human cancer. ⋯ Moreover, in univariate analysis, VEGF expression significantly affected overall and disease-free survival (P = 0.00003 and P = 0. 0004, respectively). Backward stepwise regression analysis indicated that VEGF expression was an independent prognostic factor in patients with NSCLC. These findings support the hypothesis that VEGF is an important angiogenic factor in primary NSCLC and may help in predicting the outcome of this group of cancers.
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Markedly elevated levels of macrophage colony-stimulating factor (CSF-1) in the serum and ascites of epithelial ovarian cancer patients have been previously associated with a poor prognosis. However, measurements of circulating CSF-1 cannot separate CSF-1 originating in the cancer cell from that originating in stromal macrophage or fibroblast. To study the prognosis related to expression of CSF-1 and its receptor in primary and metastatic ovarian cancers and to compare the significance of epithelial versus stromal CSF-1 expression, an immunohistochemical study of 130 ovarian carcinomas was performed. ⋯ We find that expression of the same cytokine (CSF-1) in the stroma of the primary tumors is associated with low-grade tumors and lack of strong coexpression of CSF-1 receptor and epithelial CSF-1, leading to an improved long-term outcome. This study may help explain the previous observations that elevated levels of CSF-1 in serum and ascites are associated with a worse prognosis in advanced ovarian cancer patients; the results suggest that the source of secreted CSF-1 may largely be the epithelium. The results of this study suggest that paracrine effects of stromal CSF-1 on tumor behavior contrast with those demonstrated when the tumor cell is capable of autocrine intracellular or extracellular interactions between CSF-1 and its receptor.
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Clinical Trial
A phase I study of topotecan followed sequentially by doxorubicin in patients with advanced malignancies.
Inhibitors of topoisomerase I and topoisomerase II have demonstrated synergy when administered sequentially in several tumor models while having a diminished antitumor effect when given concurrently. To explore the potential for clinical sequence-dependent synergy, we instituted a Phase I study of topotecan (a topoisomerase I inhibitor) followed by doxorubicin (a topoisomerase II inhibitor) in patients with advanced malignancies. Thirty-three patients with advanced malignancies or malignancies for whom no standard therapy exists were entered into the study. ⋯ In 7 of 10 patients, there was an increase (16.6 +/- 2.9% to 25.0 +/- 3.5%; P < 0.02) in the proportion of CD34+ cells in S-phase 24 h after the topotecan infusion and prior to doxorubicin compared to the pretreatment values, whereas 1 patient had a decrease in the proportion of CD34+ cells in S phase and 2 patients had no change. Topotecan and doxorubicin with this sequence and schedule can be given safely; the dose-limiting toxicity is hematological toxicity. Alterations in the fraction of hematopoietic progenitor CD34+ cells in S-phase may account for the increased granulocytopenia and thrombocytopenia observed at relatively low dose levels of the combination with and without G-CSF.