Clin Cancer Res
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Thrombospondin (TSP) is a Mr 450,000 multifunctional matrix glycoprotein that interferes with tumor growth, angiogenesis, and metastasis. It has recently been shown that TSP expression is enhanced by the product of the p53 gene and that a down-regulation of TSP may be observed when alterations of the p53 protein occur. Moreover, a number of studies have demonstrated a regulatory activity of p53 on human vascular endothelial growth factor (VEGF), although additional investigations will be necessary to understand their relationship. ⋯ These data support the concept that in NSCLC, p53 exerts an important role in the control of neoangiogenesis. This influence is probably mediated by VEGF. The inverse association we found between TSP I and basic FGF suggests a different role of TSP I and TSP II in the angiogenic "switch," supporting the hypothesis that especially TSP I may have a significant function in tumor angiogenesis.
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The efficacy of molecular therapies for human malignancies is limited by inadequate accumulation within solid tumors. Our laboratory has developed a novel approach that uses monoclonal antibodies (MAbs) to direct vasoactive proteins to tumor sites to increase local vascular permeability and, in turn, improve the delivery of therapeutic reagents. Previously, we demonstrated that pretreatment with immunoconjugates containing interleukin-2 (IL-2) enhances specific tumor uptake of radiolabeled MAbs without affecting normal tissues. ⋯ Pretreatment with the fusion protein increased specific tumor uptake of the MAb NR-LU-10 in A427 lung tumor-bearing mice and enhanced tumor uptake of the MAb CYT-351 in LNCaP prostate tumor-bearing mice, 2.1-fold and 1.7-fold, respectively. Finally, tumor uptake of the radiolabeled thymidine analogue 125IUdR also increased approximately 3-fold after pretreatment, indicating that this approach can be extended to small molecules such as chemotherapeutic drugs. Because TNT-3 recognizes a universal nuclear antigen accessible in degenerating and necrotic cells within all solid tumors, this strategy may be applicable to the majority of human cancers.
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Vascular endothelial growth factor (VEGF) is a cytokine that is involved in tumor angiogenesis. Wild-type p53 (wt-p53) protein has been shown in cell lines to suppress angiogenesis through thrombospondin regulation. In this study, we immunohistochemically examined the expression of VEGF, nuclear and wild-type cytoplasmic p53, bcl-2, epidermal growth factor receptor, and c-erbB-2 oncoprotein; vascular grade; proliferation index; and extent of necrosis in non-small cell lung cancer (NSCLC). ⋯ T/N stage, grade, Ki67 proliferation index, and extent of necrosis were not correlated with VEGF expression. Survival analysis showed that VEGF correlated with poor survival (P = 0.04) and was significant in node-negative cases (P = 0.03). We conclude that VEGF is an important angiogenic factor in NSCLC, its expression being dependent on wt-p53 loss.
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Approximately 30% of ovarian and breast cancers overexpress p185(c-erbB-2) with as many as 10(6) receptors/cell. Normal cells have as few as 10(4) receptors/cell. We have examined the susceptibility of SKOv3 human ovarian cancer cells to anti-c-erbB2 antibodies and immunotoxins as a function of c-erbB-2 density on the cell surface. ⋯ Importantly, tumor cells that had survived first treatment with anti-p185(c-erbB2)-RTA alone still retained sensitivity to repeat treatment with the same immunotoxin and also proved susceptible to the synergistic cytotoxicity of anti-p185(cerbB-2)-RTA in combination with anti-p170(EGFR)-RTA. Growth characteristics of the clones expressing various levels of p185(c-erbB-2) were also studied. No correlation was found between p185(c-erbB-2) expression levels and the rate of anchorage-dependent growth, anchorage-independent growth, or in vivo growth in nude mice.
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Randomized Controlled Trial Clinical Trial
Phase I trial of cremophor EL with bolus doxorubicin.
Cremophor EL (cremophor), a component of the paclitaxel formulation, can potentially reverse P-glycoprotein-associated multidrug resistance. A Phase I trial of cremophor as a 6-h infusion every 3 weeks was performed with bolus doxorubicin (50 mg/m2). The cremophor dose was escalated from 1 to 60 ml/m2. ⋯ One patient with hepatoma resistant to epirubicin achieved a near-complete response. Cremophor 45 ml/m2 over 6 h with 35 mg/m2 doxorubicin is recommended for further studies. The pharmacokinetic interaction between cremophor and doxorubicin is quantitatively similar to that described in trials of paclitaxel with doxorubicin and suggests that the cremophor in the paclitaxel formulation is responsible.