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1.
Cancer Res ; 69(18): 7347-56, 2009 Sep 15.
Article in English | MEDLINE | ID: mdl-19738071

ABSTRACT

Lenalidomide and pomalidomide have both been evaluated clinically for their properties as anticancer agents, with lenalidomide being available commercially. We previously reported that both compounds cause cell cycle arrest in Burkitt's lymphoma and multiple myeloma cell lines by increasing the level of p21(WAF-1) expression. In the present study, we unravel the molecular mechanism responsible for p21(WAF-1) up-regulation using Namalwa cells as a human lymphoma model. We show that the increase of p21(WAF-1) expression is regulated at the transcriptional level through a mechanism independent of p53. Using a combination of approaches, we show that several GC-rich binding transcription factors are involved in pomalidomide-mediated up-regulation of p21(WAF-1). Furthermore, we report that p21(WAF-1) up-regulation is associated with a switch from methylated to acetylated histone H3 on p21(WAF-1) promoter. Interestingly, lysine-specific demethylase-1 (LSD1) silencing reduced both pomalidomide and lenalidomide up-regulation of p21(WAF-1), suggesting that this histone demethylase is involved in the priming of the p21(WAF-1) promoter. Based on our findings, we propose a model in which pomalidomide and lenalidomide modify the chromatin structure of the p21(WAF-1) promoter through demethylation and acetylation of H3K9. This effect, mediated via LSD1, provides GC-rich binding transcription factors better access to DNA, followed by recruitment of RNA polymerase II and transcription activation. Taken together, our results provide new insights on the mechanism of action of pomalidomide and lenalidomide in the regulation of gene transcription, imply possible efficacy in p53 mutated and deleted cancer, and suggest new potential clinical uses as an epigenetic therapy.


Subject(s)
Cyclin-Dependent Kinase Inhibitor p21/biosynthesis , Lymphoma/drug therapy , Multiple Myeloma/drug therapy , Oxidoreductases, N-Demethylating/metabolism , Thalidomide/analogs & derivatives , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Chromatin/metabolism , Cyclin-Dependent Kinase Inhibitor p21/genetics , Gene Expression Regulation, Neoplastic/drug effects , Histone Demethylases , Histones/genetics , Histones/metabolism , Humans , Lenalidomide , Lymphoma/genetics , Lymphoma/metabolism , Multiple Myeloma/genetics , Multiple Myeloma/metabolism , Oxidoreductases, N-Demethylating/genetics , Thalidomide/pharmacology , Transcription Factors/genetics , Transcription Factors/metabolism
2.
Prostate ; 65(4): 347-54, 2005 Dec 01.
Article in English | MEDLINE | ID: mdl-16032708

ABSTRACT

BACKGROUND: Prostate cancer bone metastasis is distinguished by the predominance of osteoblastic lesions. This phenotype has been difficult to reproduce in animal models. Here, we describe a model utilizing the 22Rv1 human prostate cancer cell line that generates osteolytic lesions and a prominent spiculated periosteal osteoblastic response following intraosseous injection in scid mice. METHODS: We injected 22Rv1-luciferase prostate cancer cells directly into the tibiae of C.B-17 scid mice. We analyzed tumor growth and pathology every 2 weeks using radiographic and histologic techniques. RESULTS: X-ray analysis revealed that 22Rv1 tumors elicit a mixed-type lesion including some osteolysis and a robust induction of periosteal bone formation, in contrast to PC3M-luciferase intraosseous tumors which induce only extensive osteolysis. Micro-computerized tomographic imaging shows that 22Rv1 tumors exhibit both osteolytic and osteoblastic features which become apparent between 4 and 6 weeks post injection. There is initial disruption of the cortex and corresponding invasion of the periosteum which is associated with a vigorous osteoblastic response. Histological analysis of late stage tumors shows that the tumor has grown outside of the medullary cavity and surrounds the tibia underneath the periosteum and intermixed with spicules of woven bone which is detected in the radiographic analysis. CONCLUSIONS: The overall pattern of this model is suggestive of clinical cases of prostate cancer metastasis in which periosteal responses are noted, often in association with rapidly progressive disease. We expect that intraosseous injection of 22Rv1 cells will provide a new experimental model for the study of osteoblastic prostate cancer metastasis.


Subject(s)
Bone Neoplasms/secondary , Periosteum/pathology , Prostatic Neoplasms/pathology , Animals , Bone Neoplasms/diagnostic imaging , Cell Line, Tumor , Disease Models, Animal , Male , Mice , Mice, SCID , Osteolysis/pathology , Periosteum/diagnostic imaging , Prostatic Neoplasms/radiotherapy , Tibia/diagnostic imaging , Tibia/pathology , Tomography, X-Ray Computed , Transplantation, Heterologous
3.
Cancer Res ; 64(21): 7995-8001, 2004 Nov 01.
Article in English | MEDLINE | ID: mdl-15520207

ABSTRACT

MLN2704 is an antibody-chemotherapeutic conjugate designed to target prostate-specific membrane antigen (PSMA). PSMA is a transmembrane receptor whose expression is largely restricted to prostatic epithelium and prostate cancer cells with its expression level increasing during the progression of malignancy. MLN2704 consists of a de-immunized, monoclonal antibody that is specific for PSMA conjugated to drug maytansinoid 1 (DM1), a microtubule-depolymerizing compound. After antibody binding to PSMA and the subsequent cellular internalization of this complex, DM1 is released leading to cell death. MLN2704 has an approximate half-life of 39 hours in scid mice bearing CWR22 tumor tissue, and the antibody effectively penetrates xenograft tumor tissue. Optimization of dosage and schedule of MLN2704 administration defined interdependency between these conditions that maximized efficacy with no apparent toxicity. Tumor growth delays of approximately 100 days could be achieved on the optimized schedule of one dose of 60 mg/kg MLN2704 every 14 days for five doses (q14dx5). The unconjugated antibody (MLN591) demonstrated essentially no antitumor activity and DM1 alone or a non-PSMA targeted antibody-DM1 conjugate was only weakly active. Furthermore, we show that MLN2704 is active in a novel model of osteoblastic prostate cancer metastasis.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Glutamate Carboxypeptidase II/antagonists & inhibitors , Immunotoxins/therapeutic use , Maytansine/analogs & derivatives , Prostatic Neoplasms/therapy , Animals , Antigens, Surface , Bone Neoplasms/secondary , Humans , Male , Maytansine/therapeutic use , Mice , Neoplasm Transplantation , Transplantation, Heterologous
4.
Am J Clin Pathol ; 119(4): 472-85, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12710120

ABSTRACT

The recent clinical and commercial success of anticancer antibodies such as rituximab and trastuzumab has created great interest in antibody-based therapeutics for hematopoietic malignant neoplasms and solid tumors. Given the likelihood of lower toxic effects of antibodies that target tumor cells and have limited impact on nonmalignant bystander organs vs small molecules, the potential increased efficacy by conjugation to radioisotopes and other cellular toxins, and the ability to characterize the target with clinical laboratory diagnostics to improve the drug's clinical performance, current and future antibody therapeutics are likely to find substantial roles alone and in combination therapeutic strategies for treating patients with cancer. It also is likely that conjugation strategies will add new radiolabeled and toxin-linked products to the market to complement the recent approvals of ibritumomab tiuxetan and gemtuzumab ozogamicin. This review considers the structure of anticancer therapeutic antibodies and the techniques used to reduce their antigenicity. Efficacy and toxic effects, conjugation with isotopes and toxins, and validation of the antibody targets also are discussed. Antibodies approved by the Food and Drug Administration are described in detail, as are antibodies in late and early stages of clinical development.


Subject(s)
Antibodies, Neoplasm/therapeutic use , Antineoplastic Agents/therapeutic use , Immunotherapy , Neoplasms/therapy , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Neoplasm/chemistry , Antibodies, Neoplasm/immunology , Antibody Specificity , Antineoplastic Agents/chemistry , Antineoplastic Agents/immunology , Combined Modality Therapy , Female , Humans , Male , Neoplasms/immunology , Protein Engineering
5.
Expert Rev Anticancer Ther ; 3(1): 107-21, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12597355

ABSTRACT

The recent clinical and commercial success of anticancer antibodies, such as rituximab (Rituxan) and trastuzumab (Herceptin) has created great interest in antibody-based therapeutics for hematopoietic malignancies and solid tumors. Given the likely lower toxicity for antibodies versus small molecules, the potential increase in efficacy by conjugation to radioisotopes and other cellular toxins and the ability to characterize the target with clinical laboratory diagnostics to improve the drug's clinical performance, it is anticipated that current and future antibody therapeutics will find substantial roles alone and in combination therapy strategies for the treatment of patients with cancer. It is also likely that conjugation strategies will add new radiolabeled and toxin-linked products to the market to complement the recent approvals of ibritumomab tiuxetan (Zevalin) and gemtuzumab ozogamycin (Mylotarg). However, although there are a large number of agents in both early and later stages of clinical development, only a handful will make it through regulatory approval and become successful products. This review considers the structure of anticancer therapeutic antibodies, the techniques used to reduce their antigenicity, factors that influence efficacy and toxicity, conjugation with isotopes and toxins and antibody target validation.


Subject(s)
Antibodies, Neoplasm/therapeutic use , Immunotherapy , Neoplasms/therapy , Antibodies, Monoclonal/therapeutic use , Antibodies, Neoplasm/adverse effects , Antibodies, Neoplasm/chemistry , Clinical Trials as Topic , Drug Delivery Systems , Hematologic Neoplasms/therapy , Humans , Immunotoxins/therapeutic use , Neoplasms/immunology , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/therapeutic use
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