Sustained down-regulation of the epidermal growth factor receptor by decorin. A mechanism for controlling tumor growth in vivo.
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The small leucine-rich proteoglycan decorin interacts with the epidermal growth factor receptor (EGFR) and triggers a signaling cascade that leads to elevation of endogenous p21 and growth suppression. We demonstrate that decorin causes a sustained down-regulation of the EGFR. Upon stable expression of decorin, the EGFR number is reduced by approximately 40%, without changes in EGFR expression. However, EGFR phosphorylation is nearly completely abolished. Concurrently, decorin attenuates the EGFR-mediated mobilization of intracellular calcium and blocks the growth of tumor xenografts by down-regulating the EGFR kinase in vivo. Thus, decorin acts as an autocrine and paracrine regulator of tumor growth and could be utilized as an effective anti-cancer agent. (+info)
BBR 3464: a novel triplatinum complex, exhibiting a preclinical profile of antitumor efficacy different from cisplatin.
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Multinuclear platinum complexes represent a new class of anticancer agents, distinct in terms of DNA binding features and the profile of antitumor activity from their mononuclear counterparts, in particular cisplatin. Among complexes of this class, BBR 3464, a trinuclear platinum compound has been selected for preclinical development. In the present study, we describe the preclinical evaluation of BBR 3464 in a series of human tumor cell lines and tumor xenografts, with special emphasis on tumor types known to be resistant to cisplatin. In a panel of seven human tumor cell lines naturally resistant to cisplatin (three ovarian and four melanomas), BBR 3464 was extremely potent with IC50 values at least 20-fold lower than cisplatin. Against eight human tumor xenografts including four tumors refractory to cisplatin, BBR 3464 was confirmed to be very active with a tumor weight inhibition >80% in seven of them. The efficacy of BBR 3464 against cisplatin-resistant tumors was consistent with the ability of the drug to completely overcome resistance in three cell systems characterized by acquired resistance to cisplatin. Moreover, BBR 3464 caused a more prolonged effect than cisplatin, which was reflected by higher specific growth delay values. This prolonged effect is likely to be related to a more persistent perturbation of the cell cycle induced by BBR 3464 than by cisplatin, as shown in one ovarian tumor cell line. Finally, the profile of sensitivity to BBR 3464 within the 60-cell-lines screening panel of the National Cancer Institute, NIH (Bethesda, MD) differed from those of established drugs, thus supporting the hypothesis of a distinct mechanism of cytotoxic activity of BBR 3464. The novel trinuclear platinum complex, in light of its innovative antitumor activity profile, has the potential to become a useful clinical agent for the treatment of unresponsive tumors. (+info)
Treatment of human metastatic transitional cell carcinoma of the bladder in a murine model with the anti-vascular endothelial growth factor receptor monoclonal antibody DC101 and paclitaxel.
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Vascular endothelial cell growth factor (VEGF) regulates angiogenesis and metastasis of bladder cancer (transitional cell carcinoma, TCC) through binding to VEGF receptor-2 (VEGFR-2). In this study, we evaluated whether the anti-VEGFR monoclonal antibody (Mab) DC101 in combination with paclitaxel inhibited tumorigenesis, angiogenesis, and metastasis of human TCC growing within the bladder of athymic nude mice. In vivo therapy with Mab DC101 and paclitaxel induced significant regression of bladder tumors compared with either agent alone. Median bladder weights were reduced from 601 mg in untreated controls, 422 mg in mice treated with paclitaxel alone (P < 0.005), 361 mg in mice treated with DC101 alone (P < 0.005), and 113 mg in mice that received combination therapy (P < 0.0005). Only one of nine mice developed spontaneous lymph node metastasis after combined treatment, compared with seven of seven untreated controls (P < 0.0005), six of eight after DC101 (P < 0.01), and five of eight mice after paclitaxel (P < 0.05). Combined treatment with both paclitaxel and DC101 inhibited tumor-induced neovascularity compared with all other groups (P < 0.005), without altering the expression of VEGF or flk1. Mab DC101 and paclitaxel combined enhanced apoptosis in the tumor and endothelial cells compared with other treatment (P < 0.005). These studies indicate that Mab DC101, which blocks VEGFR-2 function, has significant efficacy against human TCC, especially when combined with the chemotherapeutic agent paclitaxel. The antitumor effect was mediated by inhibition of angiogenesis and induction of both tumor cell and endothelial cell apoptosis. (+info)
9-Nitrocamptothecin liposome aerosol treatment of melanoma and osteosarcoma lung metastases in mice.
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The response rates of relapsed osteosarcoma and melanoma pulmonary metastases to traditional i.v. chemotherapeutic regimens have been disappointing. Direct drug delivery of chemotherapy to the lungs could increase the drug concentration in the tumor area and may offer a new therapeutic approach for these patients. Previous studies demonstrated that drugs delivered to the respiratory tract in liposomal formulation resulted in high pulmonary drug concentration, reduced systemic toxicity, and reduced dosage requirements compared with parenteral and oral administration. To determine whether this approach has utility against pulmonary metastases, the efficacy of aerosol therapy with liposome-encapsulated 9-nitrocamptothecin (L-9NC) was determined using two different experimental lung metastasis models. C57BL/6 mice were treated the day after the i.v. injection of B16 melanoma cells with aerosol L-9NC for 1 h (153 microg 9-nitrocamptothecin/kg) for 5 days per week for up to 3 weeks. Aerosol L-9NC treatment resulted in a reduction in lung weights (P = 0.005) and number of tumor foci (P < 0.001). Visible tumor nodules were fewer and smaller in the 9-nitrocamptothecin-treated group than in untreated control mice (P < 0.001). Using a newly developed human osteosarcoma experimental metastasis model in nude mice, we demonstrated that aerosol L-9NC was also effective against established lung metastases. Aerosol therapy initiated on the ninth week after i.v. tumor injection and continued for 8 or 10 weeks produced highly significant reductions in the number of animals with both visible and microscopic disease (P < 0.02), the total number of tumor foci in the lungs (P < 0.005), and the size of the individual tumor nodules (P < 0.02). These data suggest that L-9NC aerosol therapy may offer significant advantage over existing methods in the treatment of melanoma and osteosarcoma pulmonary metastases. (+info)
Molecular and pharmacokinetic properties associated with the therapeutics of bcl-2 antisense oligonucleotide G3139 combined with free and liposomal doxorubicin.
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Bcl-2 is a key apoptosis-regulating protein that has been implicated in mechanisms of chemoresistance for a variety of malignancies by blocking programmed cell death. This study investigated the activity of the Bcl-2 antisense oligodeoxynucleotide (AS ODN) G3139 combined with free doxorubicin (F-DOX) or sterically stabilized liposomal doxorubicin (SL-DOX) to determine the role that drug pharmacodistribution properties may have on antitumor activity using a Bcl-2-expressing human breast solid tumor xenograft model. Administration of G3139 was able to delay the growth of MDA435/LCC6 cells compared with control ODN-treated animals; however, in all of the cases, tumors reestablished after AS ODN treatment. Western blot analyses of Bcl-2 levels of solid tumors showed a sequence-specific down-regulation of the Bcl-2 protein after four daily doses of G3139, which correlated with histological evidence of tumor cell death. Interestingly, the expression of Bcl-2 returned to pretreatment levels during the course of subsequent ODN administration, which suggested the development of resistance to continued Bcl-2 ODN treatment. The antitumor activity of ODN given in conjunction with either F-DOX or SL-DOX was also examined. The combination of G3139 and F-DOX was able to suppress the growth of MDA435/LCC6 cells beyond that obtained with either of the treatments given alone, indicative of synergistic action. Examination of the pharmacokinetics of F-DOX with systemic G3139 administration revealed that elevated tumor drug DOX levels were obtained compared with DOX treatment in the absence of G3139. This effect was sequence-specific and plasma DOX levels were unaffected by G3139 treatment, which indicated possible positive ODN-drug interactions at the tumor site. Combining G3139 with SL-DOX further increased the degree of antitumor activity. The improved efficacy of this combination was attributed to increased tumor drug levels that arise from the ability of SL-DOX to passively accumulate in solid tumors. These results suggest that additional benefits of Bcl-2 antisense ODN may be obtained when it is combined with liposomal formulations of anticancer drugs such as DOX. (+info)
Antitumor efficacy, pharmacokinetics, and biodistribution of NX 211: a low-clearance liposomal formulation of lurtotecan.
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Lurtotecan is a clinically active water-soluble camptothecin analogue that has been formulated into a low-clearance unilamellar liposome, NX 211. Comparative studies between free drug and NX 211 have been performed assessing pharmacokinetics in nude mice, tissue distribution in tumor-bearing mice, and antitumor efficacy in xenografts. Compared with lurtotecan, NX 211 demonstrated a significant increase in plasma residence time and a subsequent 1500-fold increase in the plasma area under the drug concentration curve. The volume of distribution was also greatly restricted, suggesting altered tissue distribution. Evaluation of tissues 24 h after administration of either [14C]NX 211 or [14C]lurtotecan to ES-2 tumor-bearing mice demonstrated a 40-fold increase in radiolabeled compound in the tumors of NX 211-treated mice compared with mice treated with lurtotecan. In single-dose efficacy studies, NX 211 produced a consistent 3-fold or greater increase in therapeutic index compared with lurtotecan in both the KB and ES-2 xenograft models. When compared at equitoxic levels in repeat-dose efficacy studies, NX 211 generated durable cures lasting >60 days and a 2-8-fold increase in log10 cell kill, compared with lurtotecan and topotecan, respectively. Together, these data demonstrate that NX 211 has significant therapeutic advantage over lurtotecan and that the improved antitumor activity is consistent with increased exposure and enhanced drug delivery to tumor sites. (+info)
Effects of SU101 in combination with cytotoxic agents on the growth of subcutaneous tumor xenografts.
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SU101 (leflunomide, N-[4-(trifluoromethyl)-phenyl] 5-methylisoxazole-4-carboxamide), an inhibitor of platelet-derived growth factor receptor signaling, has shown promising clinical activity in Phase I and II studies. Currently, SU101 in combination with cytotoxic agents is in late-stage clinical development for the treatment of cancers. In previous reports, efficacy in vivo versus varied tumor xenografts was observed. As part of the preclinical development of SU101 as a cancer therapy, the combination of SU101 with cytotoxic agents was studied in athymic mice bearing small, established, s.c. human tumor cell xenografts of glioblastoma (SF763T cells), lung (Calu-6 cells), or head and neck (KB cells) origin. In the SF763T model, the combination of SU101 with carmustine resulted in a statistically significant growth inhibition of 74% compared with the vehicle control; this combination was more effective than either agent alone. In the Calu-6 model, the combination of SU101, cisplatin, and etoposide resulted in a growth inhibition of 75% that was statistically greater than that of the vehicle-treated control group and groups treated with one or two agents. In the KB model, the combination of SU101, 5-fluorouracil, and cisplatin resulted in a statistically significant growth inhibition of 69% compared with the vehicle control. Treatment with one or two agents did not significantly inhibit growth in this model. Importantly, in addition to enhanced efficacy resulting from combination therapies, the combination treatments tested were well tolerated, as evidenced by lack of mortality. These data suggest that SU101 in combination with cytotoxic agents may provide clinical benefit and warrant further clinical investigation. (+info)
Opposing effects of hypoxia on expression of the angiogenic inhibitor thrombospondin 1 and the angiogenic inducer vascular endothelial growth factor.
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Tumor angiogenesis, the development of new blood vessels during malignant progression, is a regulated process that has both genetic and physiological controls. Physiologically, angiogenesis is stimulated by decreases in tissue oxygenation (i.e., hypoxia). We investigated the effect of hypoxia on the expression of two angiogenic factors reported to be genetically regulated by the p53 tumor suppressor gene: (a) the angiogenic inhibitor thrombospondin 1 (TSP-1); and (b) the angiogenic inducer vascular endothelial growth factor (VEGF). Analysis of rodent cells that differ in their p53 genotype (p53+/+ or p53-/-) indicated that in vitro exposure to hypoxia simultaneously suppressed TSP-1 and induced VEGF expression, regardless of the p53 genotype. On transformation of these cells with E1A and oncogenic H-ras, the basal level of TSP-1 expression was strongly diminished, whereas that of VEGF could still be induced by hypoxia. Consistent with these in vitro findings, sections of tumors derived from the transformed p53+/+ and p53-/- cells showed that VEGF protein overlapped with regions of hypoxia, whereas TSP-1 protein was below the limits of detection in tumor tissue. Using a panel of normal/immortalized and transformed human cells, it was found that the ability of hypoxia to inhibit TSP-1 expression depends on the cell type and/or the degree of transformation. In contrast, VEGF expression was induced by hypoxia in all of the human cell types examined. Together, these findings suggest that hypoxic and oncogenic signals could interact in the tumor microenvironment to inhibit TSP-1 and induce VEGF expression, promoting the switch to the angiogenic phenotype. (+info)