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Isaiah J Fidler

Publications and source records attributed to Isaiah J Fidler.

At least 37 records · Page 2Linked to original sources
PubMed2005

Antivascular therapy for orthotopic human ovarian carcinoma through blockade of the vascular endothelial growth factor and epidermal growth factor receptors.

PURPOSE: We determined whether the administration of the tyrosine kinase inhibitor, AEE788, which targets the epidermal growth factor receptor and the vascular endothelial growth factor receptor, alone or in combination with paclitaxel, can inhibit progressive growth of human ovarian carcinoma in the peritoneal cavity of female nude mice. EXPERIMENTAL DESIGN: Western blot analysis and immunohistochemical analysis identified the optimal dose and schedule of AEE788 therapy. In several different experiments, paclitaxel-sensitive and paclitaxel-resistant human ovarian carcinoma cells were injected into the peritoneal cavity of nude mice. Seven days later, treatment with saline (control), AEE788 alone, paclitaxel alone, or a combination of AEE788 and paclitaxel began and continued for 45 days when the mice were necropsied. In independent survival experiments, the mice were necropsied when they became moribund. RESULTS: Oral administration of AEE788 inhibited phosphorylation of the epidermal growth factor receptor and vascular endothelial growth factor receptor for up to 48 hours. Treatment with AEE788 plus paclitaxel significantly reduced tumor weight and increased survival of mice implanted with paclitaxel-sensitive cell lines compared with control mice or mice treated with AEE788 alone or paclitaxel alone. In mice implanted with paclitaxel-resistant cells, the combination therapy also significantly reduced tumor weight but did not prolong survival. The combination therapy induced apoptosis of both tumor cells and tumor-associated endothelial cells. CONCLUSIONS: The administration of AEE788 and paclitaxel inhibits the progression of human ovarian carcinoma in the peritoneal cavity of female nude mice, in part, by inducing apoptosis of tumor-associated endothelial cells.

Animals↗
PubMed2005

Expression of interleukin-8 gene in radical prostatectomy specimens is associated with advanced pathologic stage.

BACKGROUND: We previously reported that relative expression of E-cadherin, matrix metalloproteinases (MMPs)-2 and -9, and vascular endothelial growth factor (VEGF)/vascular permeability factor in radical prostatectomy specimens (RP) can distinguish organ-confined cancers from advanced prostate cancers. Here, we evaluate the expression of interleukin-8 (IL-8) and basic fibroblast growth factor (bFGF), two other genes involved in angiogenesis and metastasis, in RP specimens. METHODS: The expression level of IL-8 and bFGF mRNA in the invasive edge of 41 prostate cancers of different stages was determined using a rapid colorimetric in situ hybridization (ISH) technique. Gene expression levels of IL-8 and bFGF were correlated with the Gleason score and pathologic stage to ascertain their relationship to prostate cancer progression. RESULTS: The expression of IL-8 and bFGF genes was detected by ISH in histologically normal prostate gland epithelium as well as in glands with foci of cancer. Increased mRNA expression of IL-8 was associated with both the Gleason score and pathologic stage of tumors and distinguished organ-confined from non-confined tumors (P = 0.002). In contrast, the expression of bFGF mRNA did not correlate with the Gleason score or pathologic stage. CONCLUSIONS: Overexpression of Il-8 mRNA, but not bFGF mRNA, in RP specimens is directly associated with progression of prostate cancer.

Biomarkers, Tumor↗
PubMed2005

Antivascular therapy of human follicular thyroid cancer experimental bone metastasis by blockade of epidermal growth factor receptor and vascular growth factor receptor phosphorylation.

Patients suffering from bone metastases of follicular thyroid carcinoma (FTC) have a poor prognosis because of the lack of effective treatment strategies. The overexpression of epidermal growth factor receptor (EGFR) associated with increased vascularity has been implicated in the pathogenesis of FTC and subsequent bone metastases. We hypothesized that inhibiting the phosphorylation of the EGFR and vascular endothelial growth factor receptor (VEGFR) by AEE788, a dual tyrosine kinase inhibitor of EGFR and VEGFR, in combination with paclitaxel would inhibit experimental FTC bone lesions and preserve bone structure. We tested this hypothesis using the human WRO FTC cell line. In culture, AEE788 inhibited the EGF-mediated phosphorylation of EGFR, VEGFR2, mitogen-activated protein kinase, and Akt in culture. AEE788, alone and in combination with paclitaxel, inhibited cell growth and induced apoptosis. When WRO cells were injected into the tibia of nude mice, tumor and endothelial cells within the lesions expressed phosphorylated EGFR, VEGFR, Akt, and mitogen-activated protein kinase that were inhibited by the oral administration of AEE788. Therapy consisting of orally given AEE788 and i.p. injected paclitaxel induced a high level of apoptosis in tumor-associated endothelial cells and tumor cells with the inhibition of tumor growth in the bone and the preservation of bone structure. Collectively, these data show that blocking the phosphorylation of EGFR and VEGFR with AEE788 combined with paclitaxel can significantly inhibit experimental human FTC in the bone of nude mice.

Adenocarcinoma, Follicular↗
PubMed2005

Modulation of bone microenvironment with zoledronate enhances the therapeutic effects of STI571 and paclitaxel against experimental bone metastasis of human prostate cancer.

Prostate cancer cells metastasize to the bone where their interaction with osteoclasts and osteoblasts can lead to alterations in the structure of the bone. We determined whether the systemic administration of the bisphosphonate, zoledronate, could prevent bone lysis and halt the proliferation of human prostate cancer cells injected into the tibia of nude mice. Zoledronate did not affect the in vitro proliferation of human prostate cancer PC-3MM2 cells. The in vivo administration of zoledronate produced significant bone preservation but did not inhibit the progressive growth of PC-3MM2 cells. The systemic administration of STI571 (imatinib mesylate, Gleevec), an inhibitor of phosphorylation of the platelet-derived growth factor receptor, in combination with paclitaxel, produced apoptosis of tumor cells and bone- and tumor-associated endothelial cells. The systemic administration of zoledronate with STI571 and paclitaxel produced a significant preservation of bone structure, a decrease in tumor incidence and weight, and a decrease in incidence of lymph node metastasis. This therapeutic activity was correlated with inhibition of osteoclast function, inhibition of tumor cell proliferation, and induction of apoptosis in tumor-associated endothelial cells and tumor cells. Cancer is a heterogeneous disease that requires multimodality therapy. The present data recommend the combination of a bisphosphonate agent with protein tyrosine kinase inhibitor and an anticycling drug for the treatment of prostate cancer bone metastasis.

Animals↗
PubMed2005

Dual inhibition of epidermal growth factor receptor and vascular endothelial growth factor receptor phosphorylation by AEE788 reduces growth and metastasis of human colon carcinoma in an orthotopic nude mouse model.

We studied growth factors and their receptors in tumor cells and tumor-associated endothelial cells as the therapeutic targets in colon cancer. Immunohistochemical analysis of 13 surgical specimens of human colon adenocarcinoma revealed that both tumor cells and tumor-associated endothelial cells in 11 of the 13 specimens expressed the epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), EGF receptor (EGFR), phosphorylated EGFR (pEGFR), vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), and phosphorylated VEGFR (pVEGFR). HT29 human colon cancer cells growing orthotopically in the cecum of nude mice expressed a high level of EGF, EGFR, pEGFR, VEGF, VEGFR, and pVEGFR. Double-immunofluorescence staining found that tumor-associated mouse endothelial cells also expressed pEGFR and pVEGFR. Tumors in mice treated for 5 weeks with oral AEE788 (an inhibitor of EGFR and VEGFR tyrosine kinase) as a single agent or with CPT-11 alone were smaller (>50%) than those in control mice. Mice treated with the combination of AEE788 and CPT-11 had significantly smaller tumors (P < 0.01) and complete inhibition of lymph node metastasis. AEE788 alone or in combination with CPT-11 inhibited pEGFR, pVEGFR, and phosphorylated Akt expression on tumor-associated endothelial cells as well as on tumor cells. The combination therapy also significantly decreased microvessel density and tumor cell proliferation and increased the level of apoptosis in both tumor cells and tumor-associated endothelial cells. Collectively, these data suggest that the dual inhibition of EGFR and VEGFR signaling pathways in tumor cells and tumor-associated endothelial cells in combination with chemotherapy can provide a new approach to the treatment of colon cancer.

Animals↗
PubMed2005

Plasma protein profiling for diagnosis of pancreatic cancer reveals the presence of host response proteins.

Plasma protein profiling using separations coupled to matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) has great potential in translational research; it can be used for biomarker discovery and contribute to disease diagnosis and therapy. Previously reported biomarker searches have been done solely by MS protein profiling followed by bioinformatics analysis of the data. To add to current methods, we tested an alternative strategy for plasma protein profiling using pancreatic cancer as the model. First, offline solid-phase extraction is done with 96-well plates to fractionate and partially purify the proteins. Then, multiple profiling and identification experiments can be conducted on the same protein fractions because only 5% of the fractions are used for MALDI MS profiling. After MALDI MS analysis, the mass spectra are normalized and subjected to a peak detection algorithm. Over three sets of mass spectra acquired using different instrument variables, approximately 400 unique ion signals were detected. Classification schemes employing as many as eight individual peaks were developed using a training set with 123 members (82 cancer patients) and a blinded validation set with 125 members (57 cancer patients). The sensitivity of the study was 88%, but the specificity was significantly lower, 75%. The reason for the low specificity becomes apparent upon protein identification of the ion signals used for the classification. The identifications reveal only common serum proteins and components of the acute phase response, including serum amyloid A, alpha-1-antitrypsin, alpha-1-antichymotrypsin, and inter-alpha-trypsin inhibitor.

Acute-Phase Proteins↗
PubMed2005

Overexpression of tropomysin-related kinase B in metastatic human pancreatic cancer cells.

PURPOSE: Pancreatic adenocarcinoma is currently the fourth leading cause of cancer death in the United States, and most pancreatic cancers develop locally advanced disease or metastasis at the time of diagnosis. The mechanisms by which it invades and metastasizes are not known. EXPERIMENTAL DESIGN: To identify the genes involved in pancreatic cancer metastasis, we analyzed the gene expression profiles between highly metastatic Colo357L3.6pl and parental Colo357FG pancreatic cancer cell lines using cDNA microarrays and confirmed differential gene expression by reverse transcription-PCR, Western blotting, and immunologic analysis of 54 samples from pancreatic cancer patients. The correlation with clinical outcome was also examined. The possible signaling pathways involved with tropomyosin-related kinase B (TrkB) were analyzed. RESULTS: Our findings showed that TrkB was overexpressed in the highly metastatic Colo357L3.6pl cells, which correlated with perineural invasion (P = 0.026), positive retroperitoneal margin (P = 0.0005), and shorter latency to development of liver metastasis (Cox proportional hazard ratio, 0.3; 95% confidence interval, 0.1-0.8; P = 0.01) in patient samples. Extracellular signal-regulated kinases 1 and 2 were activated and Elk-1 and AP-1 DNA binding activity was induced in Colo357L3.6pl cells. Furthermore, interleukin 8 and vascular endothelial growth factor were more strongly expressed in Colo357L3.6pl than Colo357FG cells, and these findings were confirmed in Colo357L3.6pl and Colo357FG orthotopic tumors. CONCLUSION: These results suggest that overexpression of TrkB and activation of mitogen-activated protein kinase and AP-1, which may in turn induce the expression of vascular endothelial growth factor and interleukin 8, may mediate the cardinal clinical features of locally aggressive growth and metastasis of pancreatic cancer. Our results also imply that TrkB receptor may be a novel therapeutic target for pancreatic cancer.

Adenocarcinoma↗
PubMed2005

Inhibition of platelet-derived growth factor receptor signaling restricts the growth of human breast cancer in the bone of nude mice.

PURPOSE: Bone is a common site for breast cancer metastasis. Platelet-derived growth factor (PDGF) and PDGF receptors (PDGFR) are involved in the regulation of bone resorption. This study examined the effects of STI571 (imatinib mesylate), which inhibits PDGFR tyrosine kinase signaling, on the growth of human breast cancer cells in the bone of nude mice with consequent osteolysis. EXPERIMENTAL DESIGN: Human breast cancer MDA-MB-435 cells were injected into the tibia of female nude mice. Two weeks later the mice were treated with p.o. and injected water (control), daily p.o. STI571, weekly injection of paclitaxel, or daily STI571, plus weekly paclitaxel, for up to 8 weeks. Growth of tumors in bones and osteolysis were monitored by digital radiography and tumors were collected for histochemical analysis. RESULTS: Mice treated with STI571 or STI571 plus paclitaxel had smaller bone tumors with less lytic bone destruction than did mice treated with water or paclitaxel alone. The results of treatment with paclitaxel plus STI571 did not differ from those with STI571 alone. Immunohistochemistry showed that PDGF-A, PDGF-B, PDGFRalpha, and PDGFRbeta were expressed in the bone tumors. STI571 treatment inhibited PDGFR phosphorylation in tumor cells and tumor-associated endothelial cells, coincident with increased apoptosis, reduced proliferation, and lower microvessel density in the tumors. CONCLUSIONS: Activated PDGFRs are expressed by endothelial and tumor cells in breast cancer tumors growing in the bone of nude mice. Interfering with PDGFR signaling may be an approach to control the progressive growth of breast cancer cells and thus reduce bone lysis.

Animals↗
PubMed2005

Molecular mechanism of hTid-1, the human homolog of Drosophila tumor suppressor l(2)Tid, in the regulation of NF-kappaB activity and suppression of tumor growth.

hTid-1, a human homolog of the Drosophila tumor suppressor l(2)Tid and a novel DnaJ protein, regulates the activity of nuclear factor kappaB (NF-kappaB), but its mechanism is not established. We report here that hTid-1 strongly associated with the cytoplasmic protein complex of NF-kappaB-IkappaB through direct interaction with IkappaBalpha/beta and the IKKalpha/beta subunits of the IkappaB kinase complex. These interactions resulted in suppression of the IKK activity in a J-domain-dependent fashion and led to the cytoplasmic retention and enhanced stability of IkappaB. Overexpression of hTid-1 by using recombinant baculovirus or adenovirus led to inhibition of cell proliferation and induction of apoptosis of human osteosarcoma cells regardless of the p53 expression status. Adherent cultured cells transduced with Ad.hTid-1 detached from the dish surface. Morphological changes consistent with apoptosis and cell death were evident 48 h after Ad.EGFP-hTid-1 transduction. In contrast, cells transduced with Ad.EGFP or Ad.EGFP-hTd-1DeltaN100, a mutant that has the N-terminal J domain deletion and that lost suppressive activity on IKK, continued to proliferate. Similar data were obtained with A375 human melanoma cells. Ad.EGFP or Ad.EGFP-hTd-1DeltaN100 ex vivo-transduced A375 cells injected subcutaneously into nude mice produced growing tumors, whereas Ad.EGFP-hTid-1-transduced cells did not. Collectively, the data suggest that hTid-1 represses the activity of NF-kappaB through physical and functional interactions with the IKK complex and IkappaB and, in doing so, it modulates cell growth and death.

Adenoviridae↗
PubMed2005

Induction of apoptosis in tumor-associated endothelial cells and therapy of orthotopic human pancreatic carcinoma in nude mice.

Although gemcitabine has been accepted as the first-line chemotherapeutic reagent for advanced pancreatic cancer, improvement of response rate and survival is not sufficient and patients often develop resistance. We hypothesized that the inhibition of phosphorylation of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) on tumor cells and tumor-associated endothelial cells, combined with gemcitabine, would overcome the resistance to gemcitabine in orthotopic pancreatic tumor animal model. L3.6pl, human pancreatic cancer cells growing in the pancreas, and tumor-associated endothelial cells in microorgan environment highly expressed phosphorylated EGFR, VEGFR, and Akt, which regulates antiapoptotic mechanism. Oral administration of AEE788 (dual tyrosine kinase inhibitor against EGFR and VEGFR) inhibited the phosphorylation of EGFR, VEGFR, and Akt on tumor-associated endothelial cells as well as tumor cells. Although intraperitoneal (i.p.) injection of gemcitabine showed limited inhibitory effect on tumor growth, combination with AEE788 and gemcitabine produced nearly 95% inhibition of tumor growth in parallel with a high level of apoptosis on tumor cells and tumor-associated endothelial cells, and decreased microvascular density and proliferation rate. Collectively, these data indicate that dual inhibition of phosphorylation of EGFR and VEGFR, in combination with gemcitabine, produces apoptosis of tumor-associated endothelial cells and significantly suppresses human pancreatic cancer in nude mice.

Animals↗
PubMed2005

Construction of a novel constitutively active chimeric EGFR to identify new targets for therapy.

Tumor cells and tumor-associated endothelial cells express activated epidermal growth factor receptor (EGFR) due to production of EGF-related ligands in the tumor microenvironment. To investigate the effect of perpetual EGFR activation on endothelial cells, we developed a novel method to generate constitutively active EGFR. We fused the entire intracellular domain of the EGFR to the N-terminus of the CD3zeta component of the T-cell receptor signaling complex. Expression of the chimeric receptor CD3-EGFR in EGFR-deficient human embryonic kidney cells resulted in ligand-independent sustained EGFR phosphorylation and in the induction of Akt, mitogen-activated protein kinase, and signal transducer and activator of transcription 3 (Stat3). Next, CD3-EGFR was stably expressed in murine brain endothelial cells where it signaled for the initiation of angiogenic programs, Stat3 activation, and continuous proliferation. A comparison between brain endothelial cells encoding CD3zeta and CD3-EGFR revealed that proangiogenic phenotype was modulated by the intracellular effector Stat3 and that suppression of this downstream target with the EGFR tyrosine kinase inhibitor PKI166 could revert this phenotype. Thus, our results validate the use of chimeric constitutively active receptors to replicate critical features observed in pathophysiological processes that can expedite the identification of novel therapeutic agents targeting EGFR activation and function.

Animals↗
PubMed2005

Serum amyloid A as a tumor marker in sera of nude mice with orthotopic human pancreatic cancer and in plasma of patients with pancreatic cancer.

We screened an orthotopic nude mouse model of human pancreatic cancer for candidate serum biomarkers and examined their presence in the plasma of pancreatic cancer patients. Nude mice were injected in the pancreas with L3.9pl human pancreatic cancer cells. One week later, the mice were randomized into 4 treatment groups: i) control, saline; ii) oral STI 571; iii) intraperitoneal gemcitabine; and iv) STI 571 and gemcitabine. After 1, 2, and 3 weeks of treatment, sera and tumors were collected from mice in each group as well as uninjected mice. All sera were analyzed by surface enhanced laser desorption ionization mass spectrometry using ProteinChip technology. Protein profiles were analyzed with the Biomarker Wizard software package. The concentration of candidate proteins was evaluated in mouse sera and plasma from 135 pancreatic cancer patients, 7 pancreatitis patients, and 113 healthy volunteers. The combination therapy inhibited tumor growth. A 11.7-kDa protein peak correlating with tumor weight was purified by gel filtration, separated by SDS-PAGE, and identified as mouse serum amyloid A (SAA) by amino acid sequencing and public database searches. The expression of SAA in mouse sera was confirmed by Western blotting and correlated with tumor weight. The level of SAA in plasma of pancreatic cancer patients correlated with clinical stage and was significantly higher than in normal volunteers (mean value: 180.1 microg/ml vs 27.9 microg/ml: P<0.01) or pancreatitis patients. For SAA used as a single tumor marker with a cut-off of 75 microg/ml, the sensitivity for pancreatic cancer was 96.5% and specificity was 31.9%. Our search for specific marker proteins to identify pancreatic cancer was unsuccessful. Although SAA is not specific for pancreatic cancer and not sensitive enough to detect stage I patients, it may be a candidate biomarker for detecting and monitoring the progressive growth of pancreatic cancer.

Animals↗
PubMed2004

Epidermal growth factor receptor tyrosine kinase inhibitor does not improve paclitaxel effect in an orthotopic mouse model of lung cancer.

PURPOSE: The purpose is to evaluate whether inhibition of epidermal growth factor receptor (EGFR) activation by PKI166, an EGFR-tyrosine kinase inhibitor, affects growth of human lung cancer implanted orthotopically into the lungs of nude mice. EXPERIMENTAL DESIGN: Lungs of mice were injected with NCI-H358 human bronchioloalveolar cancer cells. In three experiments, groups of mice (n = 10 per group) were randomized 7 days after tumor implantation to receive one of the following treatments: i.p. paclitaxel 100 or 200 microg (4 or 8 mg/kg) once per week, oral PKI166 100 or 200 mg/kg three times per week, paclitaxel plus PKI166, or i.p. saline and oral PKI166-vehicle (control) for 5 weeks. Mice were killed 6.5 to 8 weeks after tumor implantation. The experiments were repeated with PC14PE6 human lung adenocarcinoma cells to assess effect on survival. RESULTS: Immunohistochemical analyses revealed the expression and phosphorylation of EGFR in the growing tumors. Treatment with PKI166 alone or in combination with paclitaxel diminished activation of EGFR on tumor cells, yet maximal therapeutic effect was observed in mice treated with paclitaxel alone. Activated mitogen-activated protein kinase and basic fibroblast growth factor expression were similar in all treatment groups. Survival in mice treated with the combination of paclitaxel and PKI166 was shorter than in those treated with paclitaxel alone. CONCLUSIONS: Our results suggest that concurrent administration of EGFR-tyrosine kinase inhibitor and chemotherapy is equivalent and may indeed be inferior to chemotherapy alone, even if EGFR is functional and its phosphorylation effectively inhibited. Our data show that the interaction of EGFR-TKIs and chemotherapy is complex and suggest that other growth factors may activate the downstream signaling events.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2004

Tumor cell and endothelial cell therapy of oral cancer by dual tyrosine kinase receptor blockade.

Expression of the epidermal growth factor (EGF) and activation of its receptor (EGFR), a tyrosine kinase, are associated with progressive growth of head and neck cancer. Expression of the vascular endothelial growth factor (VEGF) is associated with angiogenesis and progressive growth of tumor. The tyrosine kinase inhibitor NVP-AEE788 (AEE788) blocks the EGF and VEGF signaling pathways. We examined the effects of AEE788 administered alone, or with paclitaxel (Taxol), on the progression of human head and neck cancer implanted orthotopically into nude mice. Cells of two different human oral cancer lines, JMAR and MDA1986, were injected into the tongues of nude mice. Mice with established tumors were randomized to receive three times per week oral AEE788, once weekly injected paclitaxel, AEE788 plus paclitaxel, or placebo. Oral tumors were resected at necropsy. Kinase activity, cell proliferation, apoptosis, and mean vessel density were determined by immunohistochemical immunofluorescent staining. AEE788 inhibited cell growth, induced apoptosis, and reduced the phosphorylation of EGFR, VEGFR-2, AKT, and mitogen-activated protein kinase in both cell lines. Mice treated with AEE788 and AEE788 plus paclitaxel had decreased microvessel density, decreased proliferative index, and increased apoptosis. Hence, AEE788 inhibited tumor vascularization and growth and prolonged survival. Inhibition of EGFR and VEGFR phosphorylation by AEE788 effectively inhibits cellular proliferation of squamous cell carcinoma of the head and neck, induces apoptosis of tumor endothelial cells and tumor cells, and is well tolerated in mice. These data recommend the consideration of patients with head and neck cancer for inclusion in clinical trials of AEE788.

Angiogenesis Inhibitors↗
PubMed2004

Platelet-derived growth factor receptor inhibitor imatinib mesylate and docetaxel: a modular phase I trial in androgen-independent prostate cancer.

PURPOSE: To study the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate in androgen-independent prostate cancer (AIPC), alone and in combination with docetaxel, we designed a modular phase I trial. Our goals were to (1) evaluate the toxicity and maximum-tolerated dose of docetaxel with imatinib, and (2) evaluate the decline of prostate-specific antigen (PSA) induced by imatinib alone, and imatinib and docetaxel. PATIENTS AND METHODS: Twenty-eight men with AIPC and bone metastases were enrolled to receive imatinib 600 mg daily lead-in for 30 days, then imatinib 600 mg daily and one of six possible doses of docetaxel weekly for 4 weeks every 6 weeks. RESULTS: During the imatinib lead-in module, one dose-limiting toxicity (DLT) event was observed, while two (7%) of 28 had PSA decline (both < 50%). With imatinib and docetaxel, cycle 1 DLT was found in three of 12 patients at docetaxel 30 mg/m(2), in three of four patients at docetaxel 45 mg/m(2), and in five of six patients at docetaxel 35 mg/m(2). DLTs (n = 40 total events) were principally fatigue (35%) and nausea (20%). Eight (38%) of 21 had PSA decline greater than 50%, and six (29%) of 21 had PSA decline less than 50%. Serial PSA declines beyond 18 months were observed. PDGFR-expressing tumor declined on serial bone marrow biopsies with combination therapy alone. CONCLUSION: With imatinib 600 mg daily, the maximum-tolerated dose of docetaxel was determined to be 30 mg/m(2) weekly for 4 weeks every 6 weeks. Long-term responses were observed. The role of imatinib in modulating outcomes to docetaxel in AIPC is being tested in a randomized phase II trial.

Adult↗
PubMed2004

Simultaneous blockade of platelet-derived growth factor-receptor and epidermal growth factor-receptor signaling and systemic administration of paclitaxel as therapy for human prostate cancer metastasis in bone of nude mice.

Once prostate cancer metastasizes to bone, conventional chemotherapy is largely ineffective. We hypothesized that inhibition of phosphorylation of the epidermal growth factor receptor (EGF-R) and platelet-derived growth factor receptor (PDGF-R) expressed on tumor cells and tumor-associated endothelial cells, which is associated with tumor progression, in combination with paclitaxel would inhibit experimental prostate cancer bone metastasis and preserve bone structure. We tested this hypothesis in nude mice, using human PC-3MM2 prostate cancer cells. PC-3MM2 cells growing adjacent to bone tissue and endothelial cells within these lesions expressed phosphorylated EGF-R and PDGF-R alpha and -beta on their surfaces. The percentage of positive endothelial cells and the intensity of receptor expression directly correlated with proximity to bone tissue. Oral administration of PKI166 inhibited the phosphorylation of EGF-R but not PDGF-R, whereas oral administration of STI571 inhibited the phosphorylation of PDGF-R but not EGF-R. Combination therapy using oral PKI166 and STI571 with i.p. injections of paclitaxel induced a high level of apoptosis in tumor vascular endothelial cells and tumor cells in parallel with inhibition of tumor growth in the bone, preservation of bone structure, and reduction of lymph node metastasis. Collectively, these data demonstrate that blockade of phosphorylation of EGF-R and PDGF-R coupled with administration of paclitaxel significantly suppresses experimental human prostate cancer bone metastasis.

Animals↗
PubMed2004

Activation of the platelet-derived growth factor-receptor enhances survival of murine bone endothelial cells.

The activation of the microvascular endothelial cell platelet-derived growth factor (PDGF) receptor (PDGF-R) by PDGF has been implicated in neoplastic angiogenesis. Here, we established cultures of murine bone microvascular endothelial cells and examined their response to stimulation with PDGF BB ligand and to blockade of PDGF-R signaling with the tyrosine kinase inhibitor STI571 (Gleevec). The addition of STI571 to cultures of bone endothelial cells blocked PDGF BB-induced phosphorylation in a dose-dependent manner and completely abrogated the activation of downstream targets Akt and ERK1/2. Coadministration of STI571 and Taxol also induced the activation of procaspase-3 and significant apoptosis. These data suggest that phosphorylation of PDGF-R stimulates survival pathways in bone endothelial cells and that by selectively inhibiting PDGF-R signaling with STI571, the cells are rendered sensitive to Taxol treatment. The therapeutic combination of STI571 and Taxol may be a powerful tool for targeting tumor-associated endothelial cells in the skeletal compartment.

Animals↗