Potential of peroxisome proliferator-activated receptor gamma antagonist compounds as therapeutic agents for a wide range of cancer types.

PPARgamma is a therapeutic target that has been exploited for treatment of type II diabetes mellitus (T2DM) with agonist drugs. Since PPARgamma is expressed by many hematopoietic, mesodermal and epithelial cancers, agonist drugs were tested and shown to have both preclinical and clinical anticancer activities. While preclinical activity has been observed in many cancer types, clinical activity has been observed only in pilot and phase II trials in liposarcoma and prostate cancer.

Advantage of combining NLCQ-1 (NSC 709257) with radiation in treatment of human head and neck xenografts.

NLCQ-1 (NSC 709257), a hypoxia-selective cytotoxin that targets DNA through weak intercalation, was investigated for efficacy in combination with single or fractionated radiotherapy of human head and neck xenografts. A staged tumor experiment was performed in tumor-bearing female athymic nude mice that were locally irradiated with or without NLCQ-1. Tumor hypoxia was assessed by immunohistochemistry for pimonidazole adducts in tumors of varying weight.

Methods and goals for the use of in vitro and in vivo chemosensitivity testing.

Sensitive, specific, and accurate methods to assay chemosensitivity are needed to (1) screen new therapeutic agents, (2) identify patterns of chemosensitivity for different tumor types, (3) establish patterns of cross-resistance and sensitivity in treatment of naïve and relapsing tumors, (4) identify genomic and proteomic profiles associated with sensitivity, (5) correlate in vitro response with preclinical in vivo effects and clinical outcomes for a particular therapeutic agent, and (6) tailor chemotherapy regimens to individual patients. Various methods are available to achieve these end points, including several in vitro clonogenic and proliferation assays, cell metabolic activity assays, molecular assays to monitor expression of markers for responsiveness, drug resistance, and for induction of apoptosis, in vivo tumor growth and survival assays in metastatic and orthotopic models, and in vivo imaging assays. The advantages and disadvantages of the specific assays are discussed.

Peroxisome proliferator-activated receptor-gamma antagonists exhibit potent antiproliferative effects versus many hematopoietic and epithelial cancer cell lines.

Peroxisome proliferator-activated receptor-gamma ligands have preclinical and clinical anticancer activity. Most studies in this area address agonists, with relatively few reports on anticancer effects of peroxisome proliferator-activated receptor-gamma antagonists. Thus, we evaluated the two pure peroxisome proliferator-activated receptor-gamma antagonists, T0070907 and GW9662, on a panel of hematopoietic and epithelial cell lines.

Expression patterns of CEACAM5 and CEACAM6 in primary and metastatic cancers.

Background: Many breast, pancreatic, colonic and non-small-cell lung carcinoma lines express CEACAM6 (NCA-90) and CEACAM5 (carcinoembryonic antigen, CEA), and antibodies to both can affect tumor cell growth in vitro and in vivo. Here, we compare both antigens as a function of histological phenotype in breast, pancreatic, lung, ovarian, and prostatic cancers, including patient-matched normal, primary tumor, and metastatic breast and colonic cancer specimens.

Methods: Antigen expression was determined by immunohistochemistry (IHC) using tissue microarrays with MN-15 and MN-3 antibodies targeting the A1B1- and N-domains of CEACAM6, respectively, and the MN-14 antibody targeting the A3B3 domain of CEACAM5.

Inhibition of adhesion, invasion, and metastasis by antibodies targeting CEACAM6 (NCA-90) and CEACAM5 (Carcinoembryonic Antigen).

CEACAM5 and CEACAM6 are overexpressed in many cancers and are associated with adhesion and invasion. The effects of three monoclonal antibodies targeting different epitopes on these antigens (NH2-terminal [MN-3] and A1B1 domains [MN-15] shared by CEACAM5 and CEACAM6 and the A3B3 domain [MN-14] restricted to CEACAM5) were evaluated in migration, invasion, and adhesion assays in vitro using a panel of human pancreatic, breast, and colonic cancer cell lines, and in the GW-39 human colonic micrometastasis model in vivo. MN-3 Fab' and MN-15 Fab' were both effective at inhibiting cell migration.

An overview of chemosensitivity testing.

This overview chapter presents the importance of chemosensitivity testing for screening new therapeutic agents, identifying patterns of chemosensitivity for different types of tumors, establishing patterns of cross-resistance and sensitivity in treatment naive and relapsing tumors; identifying genomic and proteomic profiles associated with sensitivity; correlating in vitro response, preclinical in vivo effect, and clinical outcome associated with a particular therapeutic agent, and tailoring chemotherapy regimens to individual patients. Various assays are available to achieve these end points, including several in vitro clonogenic and proliferation assays, cell metabolic activity assays, molecular assays to monitor expression of markers for responsiveness, development of drug resistance and induction of apoptosis, in vivo tumor growth and survival assays in metastatic and orthotopic models, and in vivo imaging assays. The advantages and disadvantages of the specific assays are discussed.

Carcinoembryonic antigen antibody inhibits lung metastasis and augments chemotherapy in a human colonic carcinoma xenograft.

Purpose: In addition to its use as a blood marker for many carcinomas, elevated expression of carcinoembryonic antigen (CEA, CD66e, CEACAM5) has been implicated in various biological aspects of neoplasia, especially tumor cell adhesion, metastasis, the blocking of cellular immune mechanisms, and having antiapoptosis functions. However, it is not known if treatment with anti-CEA antibodies can affect tumor metastasis or alter the effects of cytotoxic drugs.

Methods: In vitro, human colon cancer cell lines were treated with anti-CEA MAb IgG1, hMN-14 (labetuzumab), to assess direct effects on proliferation, as well as antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC).

Technology evaluation: cT84.66, City of Hope.

Chimeric T84.66 (cT84.66) is a high affinity anti-carcinoembryonic antigen (CEA) immunoglobulin G1, that is being developed by City of Hope for the potential treatment of CEA-expressing malignancies.

Technology evaluation: Onyvax-105, Onyvax.

Onyvax, under license from the Cancer Research Campaign, is developing Onyvax-105 (105AD7), an anti-idiotype monoclonal antibody, for the potential treatment of colorectal cancer. Onyvax initiated phase II clinical trials in May 2000.

An in vitro model to optimize dose scheduling of multimodal radioimmunotherapy and chemotherapy: effects of p53 expression.

Several reports have appeared on the use of combined radioimmunotherapy (RAIT) and chemotherapy. The choice of drug to use with RAIT and how to space the two treatments has not been completely addressed. Because every patient's cancer presents with a specific molecular phenotype, we hypothesized that it may be necessary to tailor therapy based on specific gene expression.

Tumor pO2 assessments in human xenograft tumors measured by EPR oximetry: location of paramagnetic materials.

Radioantibody immunotherapy (RAIT) is a promising treatment modality but the effectiveness of this targeted low dose radiation varies from tumor to tumor. Since RAIT is an oxygen dependent treatment, baseline pO2 or growth-induced changes in the microenvironment may alter treatment response. In this pilot work we monitored tumor pO2 in untreated human xenograft tumors growing s.

Altered tumor vessel maturation and proliferation in placenta growth factor-producing tumors: potential relationship to post-therapy tumor angiogenesis and recurrence.

Cells in human tumor xenografts express similar levels of angiogenic growth factors before treatment. After radioimmunotherapy (RAIT) surviving tumor cells upregulate angiogenic growth factors, including placenta growth factor (PlGF), in a tumor-specific pattern. To determine the role of post-treatment PlGF expression on blood vessel recovery, tumor xenografts were assayed for post-RAIT vessel density (CD34+), proliferation (PCNA+) and maturity (SMA+ pericytes/mural cells).

Red marrow radiation dose adjustment using plasma FLT3-L cytokine levels: improved correlations between hematologic toxicity and bone marrow dose for radioimmunotherapy patients.

Unlabelled: Calculated red marrow absorbed dose in patients receiving radioimmunotherapy (RAIT) has not been highly predictive of the dose-limiting hematologic toxicity observed in many patient populations studied. Because patients receiving the same red marrow dose often experience different grades of toxicity, other factors might help predict the different grades of toxicity observed. One such factor may be the plasma FLT3-L (FMS-related tyrosine kinase 3 ligand, hematopoiesis stimulatory cytokine) level, which has been shown to be a better indicator of recovery of progenitor cells and, thus, red marrow radiosensitivity (because during the recovery period the progenitor cells are hyperproliferative and potentially more radiosensitive) for patients treated with previous chemotherapy than peripheral blood counts.

Abnormal expression of the angiopoietins and Tie receptors in menorrhagic endometrium.

Objective: To identify changes in expression of stimulatory and inhibitory factors when normal endometrium becomes menorrhagic.

Design: Retrospective blinded immunohistologic study.

Setting: Private research center.

Modulation of marrow proliferation and chemosensitivity by tumor-produced cytokines from syngeneic pancreatic tumor lines.

Purpose: A dynamic process exists in which hematopoietic progenitor andstromal cells interact to maintain normal hematopoiesis or to adjust to hematopoietic needs under "stress" situations. The effect that tumor-produced growth factors have on hematopoiesis has not been addressed. We postulate that an excess of tumor-produced stimulatory or inhibitory cytokines could impact marrow proliferation and sensitivity to cytotoxic agents.

Tumor-specific regulation of angiogenic growth factors and their receptors during recovery from cytotoxic therapy.

After cytotoxic treatment, up-regulation of vascular growth factors and their receptors may be crucial for tumor relapse or progression. To determine how cytotoxic therapy (radioimmunotherapy) alters expression of angiogenic growth factors and receptors, athymic mice bearing LoVo, GW-39, HT-29, or Calu3 human tumor xenografts were treated with one dose (240 microCi) of (131)I-MN-14 anti-CEA IgG or (295 microCi) (131)I-RS-7-3G11 anti-EGP-1 IgG. Tumors removed at 1-week intervals up to week 6 were probed by immunohistochemistry (n = 3-11 samples) for vascular endothelial growth factor (VEGF), placental growth factor (PlGF), flk-1 and flt-1, angiopoietin-1 and -2, and Tie-1 and -2.

Celecoxib exhibits the greatest potency amongst cyclooxygenase (COX) inhibitors for growth inhibition of COX-2-negative hematopoietic and epithelial cell lines.

Cyclooxygenase-2 (COX-2) is an important cellular target for both therapy and/or prevention of inflammatory disorders and cancer. The advent of selective COX-2 inhibitors now allows a more precise and safer treatment approach. The screening of an array of cancer cell lines for growth inhibitory effects of COX-2-selective and -nonselective inhibitors, including celecoxib (Celebrex) and rofecoxib (Vioxx), produced two unanticipated findings.

Sphingomyelin enhances chemotherapy efficacy and increases apoptosis in human colonic tumor xenografts.

Evidence suggests that ceramide, generated from a distinct subcellular pool of sphingomyelin (SM) by the action of sphingomyelinases, may be used by cells to propagate apoptotic signals in response to a variety of cytotoxic agents. Since most tumor cells have altered lipid metabolism, it is possible that the intracellular pool of SM used for signaling is decreased. To overcome this, we have attempted to increase the SM content of all intracellular compartments with exogenous SM and examined the impact on 5-fluorouracil (5FU) and irinotecan chemosensitivity.