px-478 and Neoplasms

Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor produced by tumor cells under hypoxic conditions, and a key regulator of a number of genes important in cancer biology. Over-expression of HIF-1α in human tumors is associated with poor prognosis and poor therapeutic outcomes and HIF-1α has been suggested as a novel target for cancer therapy. This article provides a review of PX-478 as the first novel HIF-1α inhibitor in clinical stage for the treatment of solid tumors.

Topics: Antineoplastic Agents; Clinical Trials, Phase I as Topic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mustard Compounds; Neoplasms; Phenylpropionates

Most solid tumors develop regions of hypoxia as they grow and outstrip their blood supply. In order to survive in the stressful hypoxic environment, tumor cells have developed a coordinated set of responses orchestrating their adaptation to hypoxia. The outcomes of the cellular responses to hypoxia are aggressive disease, resistance to therapy, and decreased patient survival. A critical mediator of the hypoxic response is the transcription factor hypoxia-inducible factor 1 (HIF-1) that upregulates expression of proteins that promote angiogenesis, anaerobic metabolism, and many other survival pathways. Regulation of HIF-1alpha, a component of the HIF-1 heterodimer, occurs at multiple levels including translation, degradation, and transcriptional activation, and serves as a testimony to the central role of HIF-1. Studies demonstrating the importance of HIF-1alpha expression for tumor survival have made HIF-1alpha an attractive target for cancer therapy. The growing l.ist of pharmacological inhibitors of HIF-1 and their varied targets mirrors the complex molecular mechanisms controlling HIF-1. In this chapter, we summarize recent findings regarding the regulation of HIF-1alpha and the progress made in identifying new therapeutic agents that inhibit HIF-1alpha.

Topics: Animals; Cell Hypoxia; Histone Deacetylase Inhibitors; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Indazoles; Mustard Compounds; Neoplasms; Phenylpropionates; Proto-Oncogene Proteins c-myc; Tumor Suppressor Protein p53

Tumor hypoxia is a common feature of many cancers. A master regulator of hypoxic response is the transcription factor hypoxia-inducible factor-1 (HIF-1). It functions as a master regulator of oxygen and undergoes conformational changes in response to varying oxygen concentrations. In this paper, we review what has been described about HIF-1: its structure, its regulation and target genes, its role in cancer, and its implication for cancer therapy.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Cell Hypoxia; Enzyme Inhibitors; Humans; Hypoxia-Inducible Factor 1; Indoles; Intercellular Signaling Peptides and Proteins; Mustard Compounds; Neoplasms; Neovascularization, Pathologic; Phenylpropionates; Pyrroles; Sunitinib

Hypoxia develops in the majority of solid tumors due to the inability of the existing vascular system to supply the growing tumor mass with adequate amounts of oxygen. A large body of clinical evidence suggests that intratumoral hypoxia correlates with the elevated aggressive behavior of cancer cells and their resistance to therapy, leading to poor patient prognoses. A heterodimeric transcription factor, hypoxia inducible factor-1 (HIF-1), has been shown to orchestrate a large number of molecular events required for the adaptation of tumor cells to hypoxia. Therefore, HIF-1 has become an attractive target for the development of anti-cancer drugs. Here, we highlight some of the recently developed small-molecule inhibitors of HIF-1 function. These drugs disrupt the HIF-1 signaling pathway through a variety of mechanisms, including the inhibition of HIF-1alpha protein synthesis, stabilization, nuclear translocation and HIF-1 transactivation of target genes.

Topics: Benzopyrans; Cell Hypoxia; Heterocyclic Compounds, 4 or More Rings; Humans; Hypoxia-Inducible Factor 1; Microtubules; Models, Biological; Mustard Compounds; Neoplasms; Phenylpropionates; Phosphoinositide-3 Kinase Inhibitors; Signal Transduction; Sirolimus; Topotecan; Tubulin Modulators

Despite reservations regarding potential toxicities, small molecule-mediated blockade of the hypoxia-inducible factor-1 transcription factor has emerged as a viable anti-cancer strategy in vivo. Recent experiments by Welsh et al. revealed unprecedented anti-tumor responses of various aggressive solid tumors to the HIF-1-inhibitory small molecule drug PX-478. Compared with other anti-cancer drugs, PX-478 had markedly improved regression, growth delay and log10 cell kill profiles, particularly against large tumors that are normally refractory to small molecule drug therapy. Importantly, pharmacokinetic and toxicity profiles were within acceptable limits, providing rationale for the clinical development of HIF-1 inhibitors in general. Though the mechanism of action for PX-478 is not completely understood, inhibition of glycolysis rather than angiogenesis appeared to be the primary mode of anti-cancer activity.

Topics: Animals; Antineoplastic Agents; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mustard Compounds; Neoplasms; Phenylpropionates; Transcription Factors

Topics: Antineoplastic Agents; Camptothecin; Digoxin; Flavonoids; Humans; Hypoxia-Inducible Factor 1; Mustard Compounds; Neoplasms; Oligonucleotides; Phenylpropionates; Polyethylene Glycols; Topotecan

PX-478 is a new agent known to inhibit the hypoxia-responsive transcription factor, HIF-1alpha, in experimental tumors. The current study was undertaken in preparation for clinical trials to determine which noninvasive imaging endpoint(s) is sensitive to this drug's actions. Dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) were used to monitor acute effects on tumor hemodynamics and cellularity, respectively. Mice bearing human xenografts were treated either with PX-478 or vehicle, and imaged over time. DW imaging was performed at three b values to generate apparent diffusion coefficient of water (ADCw) maps. For DCE-MRI, a macromolecular contrast reagent, BSA-Gd-DTPA, was used to determine vascular permeability and vascular volume fractions. PX-478 induced a dramatic reduction in tumor blood vessel permeability within 2 hours after treatment, which returned to baseline by 48 hours. The anti-VEGF antibody, Avastin, reduced both the permeability and vascular volume. PX-478 had no effect on the perfusion behavior of a drug-resistant tumor system, A-549. Tumor cellularity, estimated from ADCw, was significantly decreased 24 and 36 hours after treatment. This is the earliest significant response of ADC to therapy yet reported. Based on these preclinical findings, both of these imaging endpoints will be included in the clinical trial of PX-478.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Cell Line, Tumor; Contrast Media; Diffusion Magnetic Resonance Imaging; Female; Hemodynamics; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Image Processing, Computer-Assisted; Immunohistochemistry; Magnetic Resonance Imaging; Mice; Mice, SCID; Mustard Compounds; Necrosis; Neoplasm Transplantation; Neoplasms; Permeability; Phenylpropionates; Time Factors; Transcription Factors; Vascular Endothelial Growth Factor A

Topics: Animals; Antineoplastic Agents; Clinical Trials, Phase I as Topic; DNA-Binding Proteins; Drugs, Investigational; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Indazoles; Mustard Compounds; Neoplasms; Neovascularization, Pathologic; Nuclear Proteins; Phenylpropionates; Topotecan; Transcription Factors; Transplantation, Heterologous

The hypoxia-inducible factor-1 (HIF-1) transcription factor is an important regulator of tumor response to hypoxia that include increased angiogenesis, glycolytic metabolism, and resistance to apoptosis. HIF-1 activity is regulated by the availability of the HIF-1alpha subunit, the levels of which increase under hypoxic conditions. PX-478 (S-2-amino-3-[4'-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride) is an inhibitor of constitutive and hypoxia-induced HIF-1alpha levels and thus HIF-1 activity. We report that PX-478 given to mice suppresses HIF-1alpha levels in HT-29 human colon cancer xenografts and inhibits the expression of HIF-1 target genes including vascular endothelial growth factor and the glucose transporter-1. PX-478 shows antitumor activity against established (0.15-0.40 cm(3)) human tumor xenografts with cures of SHP-77 small cell lung cancer and log cell kills up to 3.0 for other tumors including HT-29 colon, PC-3 prostate, DU-145 prostate, MCF-7 breast, Caki-1 renal, and Panc-1 pancreatic cancers. Large (0.83 cm(3)) PC-3 prostate tumors showed 64% regression, which was greater than for smaller tumors. The antitumor response to PX-478 was positively correlated with tumor HIF-1alpha levels (P < 0.02) and was accompanied by massive apoptosis. The results show that PX-478 is an inhibitor of HIF-1alpha and HIF-1 transcription factor activity in human tumor xenografts and has marked antitumor activity against even large tumor xenografts, which correlates positively with HIF-1alpha levels.

Topics: Animals; Antineoplastic Agents; Apoptosis; Area Under Curve; Blotting, Western; Cell Line, Tumor; Erythropoietin; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Mice, SCID; Monosaccharide Transport Proteins; Mustard Compounds; Neoplasm Transplantation; Neoplasms; Phenylpropionates; Time Factors; Transcription Factors; Vascular Endothelial Growth Factor A