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J Mendelsohn

Publications and source records attributed to J Mendelsohn.

At least 55 records · Page 3Linked to original sources
PubMed1998

Therapeutic application of anti-growth factor receptor antibodies.

The application of monoclonal antibodies for the treatment of human cancer has been under extensive study for nearly two decades. With the advent of recombinant antibody technology, which makes humanized antibody or human-mouse chimeric antibody available for clinical trials, significant progress has been made in the past several years. In this article, we present an overview of recent research on anti-growth factor receptor antibodies. This research aims to modulate the function of growth factor receptors or to exploit the overexpression of these receptors on cancer cells for targeted therapy. The pharmacologic blockade of receptors with antireceptor antibody has been explored as anticancer therapy, both alone and in combination with conventional chemotherapy, or with novel inhibitors acting on various steps of signal transduction pathways. There also has been progress in research on intracellular antibodies, bispecific antibodies, antibody-fusion molecules, and antireceptor antibodies as a means of nonviral gene therapy. This review focuses primarily on monoclonal antibodies directed against the epidermal growth factor receptor family.

Animals↗
PubMed1998

Epidermal growth factor-induced growth inhibition requires Stat1 activation.

Epidermal growth factor (EGF) is a mitogen for most epithelial cells. Paradoxically, the growth of some cultured cell lines, containing high numbers of EGF receptors, are inhibited by EGF. Here we demonstrate that growth inhibition by EGF in several cell lines correlates with the activation of the signal transducer and activator of transcription (Stat) 1. In contrast, in normal fibroblasts and several cell lines that are growth stimulated by EGF, we observed no or very transient activation of Stat1. A causal association between Stat1 activation by EGF and growth inhibition was suggested by the expression of a dominant-negative Stat1 in A431 cells, resulting in the loss of Stat1 DNA binding and concomitant resistance to growth inhibition by EGF. We conclude that, in the cells examined, EGF-induced arrest of growth requires activated Stat1.

Cell Cycle↗
PubMed1998

Cell surface density of p185(c-erbB-2) determines susceptibility to anti-p185(c-erbB-2)-ricin A chain (RTA) immunotoxin therapy alone and in combination with anti-p170(EGFR)-RTA in ovarian cancer cells.

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. A panel of SKOv3 clones that expressed different densities of p185(c-erbB-2) receptor were generated through transfection with the c-erbB-2 gene. A significant correlation was found between p185(c-erbB-2) density and susceptibility to killing by anti-p185(c-erbB-2)-ricin A chain (anti-p185(c-erbB-2)-RTA) immunotoxins. With 10(5) copies/cell of p185(c-erbB-2), <10% of clonogenic ovarian cancer cells could be eliminated, whereas in clones that expressed 10(6) copies/cell of p185(c-erbB-2), 99.9% of clonogenic tumor cells were killed. In cell lines that overexpressed p185(c-erbB-2) and also expressed p170(EGFR), anti-p185(cerbB-2)-RTA and anti-p170(EGFR)-RTA immunotoxins exerted synergistic cytotoxicity. Treatment with the two immunotoxins could eliminate 99.99% of clonogenic cells. 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.

Animals↗
PubMed1997

Expression of epidermal growth factor receptor and human papillomavirus E6/E7 proteins in cervical carcinoma cells.

BACKGROUND: Epidermal growth factor receptor (EGF-R) proteins are highly expressed in many tumors, including those of the cervix. We have observed previously that the introduction of a transcription unit containing an antisense sequence for the E6/E7 genes of human papillomavirus (HPV) 18, along with a transcription unit containing a sense complementary DNA sequence for the wild-type retinoblastoma (Rb) gene, decreased the growth of human cervical carcinoma HeLa cells (HPV 18 positive) both in vitro and in vivo. To clarify the regulatory mechanisms by which this reduction in cell proliferation occurred, we studied the expression of EGF-R proteins in these cells. METHODS: Western blot and northern blot techniques were used to measure EGF-R expression, and a pulse-chase immunoprecipitation assay was used to measure the stability of EGF-R protein in HeLa cells and HeLa cells that had been transfected with the antisense E6/E7 or sense Rb sequences. Cell proliferation was measured by use of a tetrazolium-based colorimetric assay for numbers of viable cells. RESULTS: The introduction of sense Rb or antisense E6/E7 transcription units or a combination of these two transcription units into HeLa cells dramatically decreased the level of EGF-R proteins in these cells; EGF-R levels were not affected at the transcriptional level but at the post-transcriptional level. Addition of the anti-EGF-R-specific monoclonal antibody 225mAb to HeLa cells caused 53% (95% confidence interval = 44%-62%) growth inhibition. CONCLUSIONS: These results suggest that HeLa cervical carcinoma cells are dependent on EGF-R for proliferation and that changes in functional levels of the E6/E7 HPV proteins and endogenous Rb proteins may alter the growth rate of cervical cancer cell lines by reducing the stability of EGF-R at the post-transcriptional level.

Blotting, Northern↗
PubMed1997

Basic fibroblast growth factor causes growth arrest in MCF-7 human breast cancer cells while inducing both mitogenic and inhibitory G1 events.

Basic fibroblast growth factor (bFGF), a classical mitogen in fibroblasts and endothelial cells, inhibits the proliferation of MCF-7 and other human breast cancer cell lines. To explain this paradoxic effect, we investigated the effects of bFGF on cyclins and protein members of cyclin complexes that exert positive and negative control on the progression of cells through the G1 phase of the cell cycle. bFGF induced an increase in cyclin D1, cyclin E, and cyclin-dependent kinase 4 (cdk4) protein levels in a bFGF dose-dependent manner. However, bFGF also induced a heat-stable, transferable cytoplasmic factor in MCF-7 cells that inhibited the histone H1 kinase activity of reconstituted cyclin E-cdk2 and cyclin A-cdk2 complexes from Mv1Lu mink lung epithelial cells. The appearance of this inhibitor correlated with a bFGF dose- and time-dependent increase in the levels of cdk inhibitor p21(WAF1/CIP1) mRNA and protein. The increase in the level of p21(WAF1/CIP1) was associated with the disappearance of the rapidly migrating, activated form of cdk2 from cell lysates, dephosphorylation of the retinoblastoma protein (Rb), and a decrease in cyclin A levels. These changes were represented in the cyclin D1 and E complexes by an increased association with p21(WAF1/CIP1), proliferating cell nuclear antigen (PCNA), and the inactive form of cdk2, without an absolute change in cellular PCNA levels and by a switch in the association of cyclin D1 complexes with the hyperphosphorylated form to the dephosphorylated form of Rb. These experiments demonstrate that stimulation of MCF-7 cells with bFGF, although resulting in up-regulation of G1 proteins responsible for mitogenic events, also induces a concomitant decrease in cyclin A levels and an increase in p21(WAF1/CIP1) mRNA and protein and results in inactivation of cdk2, dephosphorylation of Rb, and a segregation of PCNA to the G1 cyclin complexes. The dual, conflicting signaling by bFGF results in a net inhibitory phenotype in these cells. These experiments suggest a pleiotropic role for bFGF in breast cancer.

Blotting, Western↗
PubMed1997

Type I receptor tyrosine kinases as targets for therapy in breast cancer.

Breast carcinomas express high levels of type I tyrosine kinase receptors and their ligands. For these reason therapies directed at these receptors have the potential to be useful anticancer agents. A series of monoclonal antibodies (MAbs)3 directed against the EGF receptor and the closely related erbB2/HER2/neu receptor are currently under evaluation. These MAbs have shown promising preclinical activity and "chimeric" and "humanized" MAbs have been produced in order to obviate the problem of host immune reactions. These antibodies are currently being tested in clinical trials either alone or in combination with chemotherapeutic agents. Clinical activity with anti-HER2/neu MAbs has been documented in patients with advanced breast cancer. In addition, compounds that inhibit receptor tyrosine kinases have shown significant preclinical activity and are potential candidates for clinical testing.

Animals↗
PubMed1997

Epidermal growth factor receptor inhibition by a monoclonal antibody as anticancer therapy.

Monoclonal antibody (mAb) 225 against the human epidermal growth factor receptor blocks activation of receptor tyrosine kinase. This retards or arrests cell cycle progression, with accumulation of cells in G1 phase. The mechanism of growth inhibition involves increased levels of p27KIP1 and inhibition of cyclin-dependent kinase-2 activity. mAb in combination with chemotherapy exhibits a synergistic antitumor activity, with successful eradication of well-established tumor xenografts that resist treatment with either mAb or drug alone. A Phase I clinical trial has established the safety of repeated administration of human:mouse chimeric mAb 225 at concentrations that maintain receptor-saturating blood levels for up to 3 months. Phase I trials exploring mAb 225 treatment in combination with doxorubicin, cisplatin, or paclitaxel are ongoing.

Antibodies, Monoclonal↗
PubMed1997

Reciprocal changes in p27(Kip1) and p21(Cip1) in growth inhibition mediated by blockade or overstimulation of epidermal growth factor receptors.

Many human epithelial tumors express high levels of epidermal growth factor (EGF) receptors. A human-mouse chimeric version of anti-EGF receptor monoclonal antibody (mAb) C225, which blocks receptor activation and produces inhibition of cell proliferation, is currently being investigated in clinical trials. When cells bear high numbers of EGF receptors, either complete blockade of receptors with mAb 225 or full activation of receptors with EGF results in inhibition of proliferation. In the present study, we have explored the molecular mechanisms explaining how a receptor inhibitor, mAb 225, and a receptor activator, EGF, can both produce growth inhibition of A431 human squamous epithelial carcinoma cells. We reported previously that inhibition of A431 cells by EGF is associated with up-regulation of p21(Cip1). We now demonstrate that mAb 255-mediated inhibition is associated with up-regulation of p27(Kip1), which binds to and inactivates cyclin-dependent kinase-2 activity and produces cell cycle arrest in G1. Furthermore, inhibition by mAb 225 can be overcome by titrating the cultures with increasing concentrations of EGF, which is accompanied by a concurrent fall in the level of p27(Kip1). At properly titrated concentrations of mAb 225 and EGF, the inhibitory activities of both mAb 225 and EGF are counterbalanced and abolished. When EGF concentrations reach levels high enough to compete with mAb to produce near-saturating levels of receptor activation, p27(Kip1) falls below basal levels; however, the concomitant marked rise in the level of p21(Cip1) results in growth inhibition. Our data suggest that although p27(Kip1) and p21(Cip1) are induced and act independently, they play reciprocal roles in mediating inhibition of A431 cell growth by blockade of EGF receptors with mAb 225 and by activation of receptors with saturating concentrations of EGF.

Animals↗
PubMed1997

PD153035, a tyrosine kinase inhibitor, prevents epidermal growth factor receptor activation and inhibits growth of cancer cells in a receptor number-dependent manner.

PD153035 is reported to be a specific and potent inhibitor of the epidermal growth factor (EGF) receptor tyrosine kinase and, to a lesser degree, of the closely related HER2/neu receptor. We show that PD153035 inhibits EGF-dependent EGF receptor phosphorylation and suppresses the proliferation and clonogenicity of a wide panel of EGF receptor-overexpressing human cancer cell lines. EGF receptor autophosphorylation in response to exogenous EGF was completely inhibited at PD153035 concentrations of >75 nM in cells overexpressing the EGF receptor. In contrast, PD153035 only reduced heregulin-dependent tyrosine phosphorylation in HER2/neu-overexpressing cell lines at significantly higher concentrations (1400-2800 nM). PD153035 exposure did not affect the expression of either EGF receptors or HER2/neu. PD153035 caused a dose-dependent growth inhibition of EGF receptor-overexpressing cell lines at low micromolar concentrations, and the IC50 in monolayer cultures was less than 1 microM in most cell lines tested. At doses of up to 2.5 microM, the IC50 for HER2/neu-overexpressing cells was not reached. In colony-forming assays, the PD153035 growth-inhibitory activity in cultures driven by endogenous (autocrine) ligand was correlated with EGF receptor number, with higher activity in cells expressing higher numbers of EGF receptors and only minimal activity in cells expressing normal numbers of EGF receptors but high HER2/neu levels. PD153053 also abolished all growth effects mediated by the addition of exogenous EGF; this condition could be reversed upon removal of the compound. Cotreatment with C225, an anti-EGF receptor-blocking monoclonal antibody, further enhanced the antitumor activity of PD153035, suggesting mechanisms of action for C225 other than competition with ligand binding. This latter finding also suggests that combined anti-EGF receptor strategies may be of enhanced benefit against tumors with high levels of EGF receptor expression.

Adenocarcinoma↗
PubMed1996

Antitumor activity of combined blockade of epidermal growth factor receptor and protein kinase A.

BACKGROUND: Epidermal growth factor (EGF)-related proteins, such as transforming growth factor-alpha (TGF-alpha), control cancer cell growth through hormonal pathways (i.e., autocrine [hormone acts on cell that produces it] and paracrine [hormone acts on nearby cells] pathways). Overexpression of TGF-alpha and/or its receptor (EGFR) has been detected in human cancers. The blockade of EGFR activation by the use of anti-EGFR monoclonal antibodies (MAbs) has been proposed as a potential anticancer therapy. The type I cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKAI) is generally overexpressed in human cancer cells and is involved in neoplastic transformation. Inhibition of PKAI by selective cAMP analogues, such as 8-chloro-cAMP (8-CI-cAMP), induces growth inhibition in various human cancer cell lines. PURPOSE: On the basis of our previous observations of a cooperative anti-proliferative effect of anti-EGFR Mab 528 and 8-Cl-cAMP in human cancer cell lines in vitro, we evaluated the anticancer activity in vivo of the combination of an anti-EGFR MAb (MAb C225) and 8-Cl-cAMP. METHODS: Athymic mice were injected subcutaneously with 10(7) human colon carcinoma GEO cells. After 7 days, when established tumor xenografts of 0.30-0.35 cm3 were detectable, 10-15 mice per group were treated intraperitoneally twice weekly with different doses of 8-Cl-cAMP and/or MAb C225. Cancer cell expression of various growth factors was evaluated by immunohistochemical analysis in tumors obtained from control and treated mice. Data were evaluated for statistical significance using the Student's t test and the Mantel-Cox logrank test. All P values represent two-sided tests of statistical significance. RESULTS: A 5-week treatment with low doses of 8-Cl-cAMP (0.5 mg/dose) and MAb C225 (0.25 mg/dose) blocked GEO tumor growth (compared with that in control mice; P < .00001) and suppressed cancer cell production of autocrine growth factors, such as TGF-alpha, amphiregulin, and CRIPTO, and of angiogenic (promotes new blood vessel formation) factors, such as vascular endothelial growth factor and basic fibroblast growth factor, with no signs of toxicity. Control and 8-Cl-cAMP (0.5 mg/dose)-treated mice died within 9-10 weeks after tumor cell injection. In MAb C225 (0.25 mg/dose)-treated mice, GEO tumors resumed a growth rate comparable to that in control animals within 3 weeks following the end of treatment and the mice died between 11 and 20 weeks after tumor cell injection. GEO tumor growth was significantly delayed in the MAb C225 plus 8-Cl-cAMP treatment group (P < .00001) and was accompanied by a prolonged survival of mice (P < .00001) as compared with the control group. CONCLUSIONS: Long-term treatment with a combination of agents that selectively inhibit two intracellular signal-transduction enzymes, such as the PKAI serine-threonine kinase and the EGFR tyrosine kinase, has anticancer activity in vivo, reflected by suppression of tumor proliferation and angiogenesis, with no signs of toxicity. IMPLICATIONS: Since these inhibitors of intracellular mitogenic (growth-stimulating) signaling have a different mechanism(s) of action and do not antagonize the effects of cytotoxic therapy, a combination of anti-EGFR MAb C225 and 8-Cl-cAMP should be investigated as a nontoxic, long-term treatment for cancer patients following chemotherapy.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

Anti-epidermal growth factor receptor monoclonal antibody 225 up-regulates p27KIP1 and induces G1 arrest in prostatic cancer cell line DU145.

Autocrine production of transforming growth factor alpha and overexpression of the epidermal growth factor receptor (EGFR) may contribute to androgen-independent prostatic cancer growth at both primary and metastatic sites. Previously, we showed that human EGFR-blocking monoclonal antibody mAb225 inhibited the growth of DU145 human prostatic cancer cells. Here we explore the hypothesis that mAb225 may act by interfering with cell cycle traversal in these cells. Treatment with mAb225 induced G1 arrest, which was accompanied by a marked decrease in CDK2-, cyclin A-, and cyclin E-associated histone H1 kinase activities, and a sustained increase in cell cycle inhibitor p27KIP1. The increased p27KIP1 levels were attributable to elevation of both transcription and translation. CDK2 associated with p27KIP1 was increased in mAb225-treated DU145 cells. The retinoblastoma-related protein p130 remained hypophosphorylated in these retinoblastoma-negative cells. These studies demonstrate that the antiproliferative effect of EGFR blockade in DU145 cells may be mediated by up-regulation of p27KIP1 at both the mRNA and protein levels.

Antibodies, Monoclonal↗
PubMed1996

Involvement of B lymphocytes in the growth inhibition of human pulmonary melanoma metastases in athymic nu/nu mice by an antibody-lymphotoxin fusion protein.

Antibody-cytokine fusion proteins can target biologically active cytokines to various tumor sites, achieving local concentrations sufficient to induce host immune responses leading to tumor elimination. Here, we demonstrate the therapeutic efficacy of a tumor-specific antibody-lymphotoxin fusion protein (ch225-LT) on xenografted pulmonary metastases of human melanoma. In vitro studies indicated a direct cytotoxic effect of such construacts on melanoma cells via the induction of apoptosis, as demonstrated by cell cycle analysis and DNA fragmentation. However, ch225-LT lacked any therapeutic effect in immune deficient C.B17 scid/beige and scid/scid mice, indicating the insufficiency of this direct mechanism in vivo. In contrast, in athymic nu/nu mice, ch225-LT completely inhibited outgrowth of the xenografted tumor. This therapeutic effect was accompanied by infiltrations of CD45+, Mac-1+, and asialo-GM1+ cells into the tumor; B220+ cells were present in the surrounding tissue and the periphery of the tumor. The functional role of asialo-GM2+ cells was confirmed by in vivo depletion studies. Our data indicate that an antibody-lymphotoxin fusion protein effectively inhibits the growth of disseminated melanoma metastases by mechanisms that function in the absence of mature T cells, but require B, NK, and other asialo-GM1+ cells.

Animals↗
PubMed1996

Involvement of p27KIP1 in G1 arrest mediated by an anti-epidermal growth factor receptor monoclonal antibody.

Activation of the cyclin dependent kinases (CDK4/CDK6 and CDK2) is required for G1 phase progression and entry into S-phase. The activation of these kinases is regulated by checkpoints that monitor environmental and intracellular conditions. Progression into S-phase is controlled, in part, by the availability of growth factors, and we have investigated the relationship between growth factor availability and the activation of the CDK kinases. Blocking activation of epidermal growth factor (EGF) receptor tyrosine kinase with anti-EGF receptor monoclonal antibody (mAb) 225 induces G1 phase cell cycle arrest in DiFi human colon adenocarcinoma cells. When DiFi cells are treated with mAb 225 for 24 h, we observe marked decreases in the activities of CDK2 kinase and cyclin E-associated CDK kinase which are not accompanied by reduced levels of cyclin E and CDK2 proteins. However, the amount of cyclin/CDK kinase inhibitor p27KIP1 increases in the mAb-treated cells and p27KIP1 is bound to CDK2 in increasing amounts. Immunodepletion of p27KIP1 removes an inhibitory activity from lysates of mAb-treated cells: the immunodepleted and heated lysates lose the capacity to inhibit cyclin E/CDK2 activity in an in vitro assay. The results suggest that G1 arrest in the cell cycle induced by EGF receptor blockade involves p27KIP1.

Antibodies, Monoclonal↗
PubMed1996

Eradication of human hepatic and pulmonary melanoma metastases in SCID mice by antibody-interleukin 2 fusion proteins.

Antibody-cytokine fusion proteins combine the unique targeting ability of antibodies with the multifunctional activity of cytokines. Here, we demonstrate the therapeutic efficacy of such constructs for the treatment of hepatic and pulmonary metastases of different melanoma cell lines. Two antibody-interleukin 2 (IL-2) fusion proteins, ch225-IL2 and ch14.18-IL2, constructed by fusion of a synthetic sequence coding for human IL-2 to the carboxyl end of the Cgamma1 gene of the corresponding antibodies, were tested for their therapeutic efficacy against xenografted human melanoma in vivo. Tumor-specific fusion proteins completely inhibited the growth of hepatic and pulmonary metastases in C.B-17 scid/scid mice previously reconstituted with human lymphokine-activated killer cells, whereas treatment with combinations of the corresponding antibodies plus recombinant IL-2 only reduced the tumor load. Even when treatment with fusion proteins was delayed up to 8 days after inoculation of tumor cells, it still resulted in complete eradication of micrometastases that were established at that time point. Selection of tumor cell lines expressing or lacking the targeted antigen of the administered fusion protein proved the specificity of the observed antitumor effect. Biodistribution analysis demonstrated that the tumor-specific fusion protein accumulated not only in subcutaneous tumors but also in lungs and livers affected with micrometastases. Survival times of animals treated with the fusion protein were more than doubled as compared to those treated with the combination of the corresponding antibody plus IL-2. Our data demonstrate that an immunotherapeutic approach using cytokines targeted by antibodies to tumor sites has potent effects against disseminated human melanoma.

Animals↗
PubMed1996

Autocrine regulation of membrane transforming growth factor-alpha cleavage.

Transforming growth factor alpha (TGF-alpha) is biosynthesized as a membrane-bound precursor protein, pro-TGF-alpha, that undergoes sequential endoproteolytic cleavages to release a soluble form of the factor. In the present study, we have analyzed the biosynthesis and regulation of TGF-alpha production in human tumor-derived cell lines that endogenously express pro-TGF-alpha and the epidermal growth factor (EGF) receptor. These cells biosynthesized membrane-anchored forms of the TGF-alpha that accumulated on the cell surface. Membrane-bound pro-TGF-alpha interacted with the EGF receptor, and complexes of receptor and pro-TGF-alpha contained tyrosine-phosphorylated receptor. Activation of the EGF receptor by soluble EGF or TGF-alpha had a dual effect on TGF-alpha production: an increase in pro-TGF-alpha mRNA levels and an increase in pro-TGF-alpha cleavage. These effects were largely prevented by preincubation with an anti-EGF receptor monoclonal antibody that blocked ligand binding. Growth factor autoinduction of cleavage could be stimulated by several second messenger pathways that are activated by the EGF receptor, including protein kinase C and intracellular calcium, and by other alternative mechanisms. EGF-stimulated cleavage of pro-TGF-alpha could be partially blocked by inhibition of these second messenger pathways. These results suggest that juxtacrine stimulation takes place in human tumor cells that coexpress both the EGF receptor and membrane-anchored TGF-alpha and that TGF-alpha is able to induce its own endoproteolytic cleavage by activating the EGF receptor.

Animals↗
PubMed1996

The epidermal growth factor receptor and its ligands as therapeutic targets in human tumors.

The epidermal growth factor receptor (EGFR) is detected on many non-haematopoietic tissues and is frequently overexpressed in human tumors. With its ligand, TGF-alpha, it forms a well-defined autocrine growth loop. Several clinical approaches, using EGFR as a therapeutic target, are being investigated, particularly monoclonal antibodies combined with chemotherapy, and pharmacological inhibition of downstream components of the EGFR signaling pathway.

Animals↗
PubMed1996

The biologic effects of C225, a chimeric monoclonal antibody to the EGFR, on human prostate carcinoma.

For prostate cancer, a correlation exists between overexpression of the epidermal growth factor receptor (EGFR) and poor clinical prognosis. In addition, late-stage metastatic disease is characterized by a change from a paracrine to an autocrine mode of expression for TGF-alpha, the ligand for the EGFR. These observations suggest that activation of the EGFR may be important for the growth of prostatic carcinoma in situ, and blockade of the receptor-ligand interaction may offer a means of therapeutic intervention for this disease. We describe the biologic effects of a chimeric anti-EGFR monoclonal antibody, C225, on several human prostate tumor cell lines in culture and the tumor inhibitory properties of the antibody for the treatment of human prostate carcinoma xenografts in nude mice. In vitro analysis of the EGFR from androgen-responsive and independent prostatic carcinoma cell lines revealed that C225 blocked EGF-induced receptor activation and induced internalization of the receptor. In vivo, a treatment regimen of C225 alone or antibody plus doxorubicin significantly inhibited tumor progression of well-established DU145 and PC-3 xenografts in nude mice. These results suggest that C225 may have utility for the treatment of human prostate carcinoma in a clinical setting.

Animals↗