Feasibility trial of methotrexate-paclitaxel as a second line therapy in advanced urothelial cancer.

To evaluate the clinical value of the concurrent use of methotrexate administered immediately before paclitaxel, we investigated the efficacy and toxicity of this two-drug combination administered as palliative second line therapy in patients with advanced urothelial cancer. The design of the schedule and sequence used was based on our previous preclinical data from a comparative study on sequential combinations of paclitaxel and methotrexate in a human bladder cancer cell line. As a confirmation study, we further extended our analysis of in vitro synergism.

Capecitabine (Xeloda) in combination with oxaliplatin: a phase I, dose-escalation study in patients with advanced or metastatic solid tumors.

Objectives: This phase I, dose-escalation study was conducted to determine the recommended dose of intermittent oral capecitabine in combination with a fixed dose of i.v. oxaliplatin.

Targeting epidermal growth factor receptor in lung cancer.

Among the most promising agents in clinical development to treat non-small-cell lung cancer (NSCLC) are the epidermal growth factor receptor (EGFR) targeting agents. A series of recent studies have demonstrated the activity of anti-EGFR targeted therapies for NSCLC. In advanced NSCLC that is refractory to chemotherapy, antitumor responses have been reported with EGFR tyrosine kinase inhibitors (ZD1839 and OSI-774).

Anti-HER2 immunoliposomes: enhanced efficacy attributable to targeted delivery.

Purpose: Anti-HER2 immunoliposomes combine the tumor-targeting of certain anti-HER2 monoclonal antibodies (MAbs) with the pharmacokinetic and drug delivery capabilities of sterically stabilized liposomes. We previously showed that anti-HER2 immunoliposomes bind efficiently to and internalize in HER2-overexpressing cells in vitro, resulting in intracellular drug delivery.

Experimental Design: Here we describe the pharmacokinetics and therapeutic efficacy of anti-HER2 immunoliposomes containing doxorubicin (dox) in a series of animal models.

NH(2)-terminal truncated HER-2 protein but not full-length receptor is associated with nodal metastasis in human breast cancer.

Background: The full-length receptor p185HER-2 undergoes a metalloprotease-dependent cleavage producing a membrane-associated fragment (p95HER-2) in cultured breast cancer cells. P95HER-2 has potentially enhanced signaling activity, but its expression and role in human breast cancer is poorly characterized.

Purpose: The purpose of this project was to characterize the expression of p95HER-2 in primary breast cancers and nodal metastasis, and to study association with clinicopathological factors.

Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition.

Purpose: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Iressa; AstraZeneca Pharmaceuticals, Alderley Park, United Kingdom) is under development as an anticancer agent. We studied the pharmacodynamic effects of ZD1839 on EGFR in the skin, an EGFR-dependent tissue, in cancer patients participating in ZD1839 phase I clinical trials.

Patients And Methods: We studied 104 pre- and/or on-ZD1839 therapy ( approximately at day 28 of therapy) skin biopsies from 65 patients receiving escalating doses of daily oral ZD1839.

Pharmacodynamic studies with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839.

ZD1839 is an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that blocks signal transduction pathways implicated in the proliferation and survival of cancer cells, and other host-dependent processes promoting cancer growth. Based on its promising preclinical antitumor activity and favorable toxicity profile, ZD1839 has recently entered clinical trials. A particular challenge in the clinical development of this exciting compound is to explore its biological (pharmacodynamic) activity against the EGFR and receptor-dependent processes in serial biopsies.

Mechanism of action of trastuzumab and scientific update.

The humanized anti-p185(HER2) monoclonal antibody trastuzumab has been shown to effectively inhibit the growth of HER2-overexpressing breast cancer cells in vivo and in vitro. The treatment of cancer cells with trastuzumab results in downregulation of the HER2 receptor. Further downstream cellular events include the accumulation of the cyclin-dependent kinase inhibitor p27 and cell cycle arrest.

Herceptin alone or in combination with chemotherapy in the treatment of HER2-positive metastatic breast cancer: pivotal trials.

Large pivotal phase II and III clinical trials investigated the therapeutic efficacy and safety of the humanized anti-HER2 monoclonal antibody, Herceptin, alone and in combination with standard chemotherapy, respectively, in HER2-positive metastatic breast cancer. Eligible patients were HER2 2+ and 3+ overexpressors, as determined by immunohistochemistry (IHC). Herceptin was well tolerated in both trials.

A feasibility study of carboplatin with fixed dose of gemcitabine in "unfit" patients with advanced bladder cancer.

For the purpose of a subsequent phase II/III European Organization for Research and Treatment of Cancer (EORTC) trial, a gemcitabine/carboplatin feasibility study in "unfit" patients with advanced urothelial cell cancer was conducted. Gemcitabine was given at 1000 mg/m(2) days 1 and 8 with carboplatin (area under the curve (AUC) 4.5 or 5) day 1 every 21 days.

Metalloprotease-dependent protransforming growth factor-alpha ectodomain shedding in the absence of tumor necrosis factor-alpha-converting enzyme.

Zinc-dependent metalloproteases can mediate the shedding of the extracellular domain of many unrelated transmembrane proteins from the cell surface. In most instances, this process, also known as ectodomain shedding, is regulated via protein kinase C (PKC). The tumor necrosis factor alpha-converting enzyme (TACE) was the first protease involved in regulated protein ectodomain shedding identified.

The EGFR as a target for anticancer therapy--focus on cetuximab.

The anti-epidermal-growth-factor-receptor (EGFR) monoclonal antibody cetuximab specifically binds to the EGFR with high affinity, blocking growth-factor binding, receptor activation and subsequent signal-transduction events leading to cell proliferation. Preclinical studies, both in vitro and in vivo, have shown that cetuximab enhances the antitumour effects of chemotherapy as well as radiotherapy by inhibiting cell proliferation, angiogenesis and metastasis and by promoting apoptosis. As of June 2000, 526 patients with advanced solid tumours were treated with cetuximab in phase I/II clinical trials.

Interleukin-2 enhances the natural killer cell response to Herceptin-coated Her2/neu-positive breast cancer cells.

The Her2/neu (c-erbB-2) oncogene encodes a 185-kDa protein tyrosine kinase which is overexpressed in 20% of breast adenocarcinomas and is recognized by a humanized anti-Her2/neu monoclonal antibody (mAb) (rhu4D5 or Herceptin). Natural killer (NK) cells are capable of mediating antibody-dependent cell cytotoxicity (ADCC) against antibody-coated targets via their expression of a low-affinity receptor for IgG (FcgammaRIII or CD16). NK cells can be expanded in cancer patients via the administration of low-dose interleukin-2 (IL-2) and become potent cytotoxic effectors following exposure to high doses of IL-2.

Activated extracellular signal-regulated kinases: association with epidermal growth factor receptor/transforming growth factor alpha expression in head and neck squamous carcinoma and inhibition by anti-epidermal growth factor receptor treatments.

The expression of the activated mitogen-activated kinases/extracellular signal-regulated kinases (ERKs) ERK1 and ERK2 was characterized in 101 humanhead and neck squamous carcinoma specimens. Activated ERK1/2were detected at different levels in the majority of these tumors, as assayed by immunostaining with an antibody specific for the dually phosphorylated and activated ERK1 and ERK2. ERK1/2 activation levels were higher in tumors with advanced regional lymph node metastasis (P = 0.

Phase I and II clinical trials of trastuzumab.

This report summarizes the efficacy of trastuzumab (Herceptin) based on its completed clinical trial program in patients with HER2-positive metastatic breast cancer for phase I and II studies which have been completed to date and were integral in the submission that led to approval of trastuzumab for clinical use in the USA. There were three small-scale, phase I clinical trials conducted, which were primarily designed to determine the safety and pharmacokinetics of trastuzumab (10-500 mg) administered i.v.

Mechanism of action of anti-HER2 monoclonal antibodies.

The search for new methods of treating cancer, combined with advances in our understanding of carcinogenesis, molecular biology and technology, has resulted in the development of novel biologic agents with proven clinical efficacy. One such agent is trastuzumab (Herceptin), a humanized monoclonal antibody that targets the human epidermal growth factor receptor-2 (HER2). HER2 is a member of a family of receptors that interact with each other and various ligands to stimulate various intracellular signal transduction pathways involved in cell growth control.

The EGF receptor family as targets for cancer therapy.

Human carcinomas frequently express high levels of receptors in the EGF receptor family, and overexpression of at least two of these receptors, the EGF receptor (EGFr) and closely related ErbB2, has been associated with a more aggressive clinical behavior. Further, transfection or activation of high levels of these two receptors in nonmalignant cell lines can lead to a transformed phenotype. For these reasons therapies directed at preventing the function of these receptors have the potential to be useful anti-cancer treatments.

Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells.

HER2 is a ligand-less tyrosine kinase receptor of the ErbB family that is frequently overexpressed in breast cancer. It undergoes proteolytic cleavage that results in the release of the extracellular domain and the production of a truncated membrane-bound fragment, p95. We show that HER2 shedding is activated by 4-aminophenylmercuric acetate (APMA), a well-known matrix metalloprotease activator, in HER2-overexpressing breast cancer cells.

Weekly docetaxel in breast cancer: applying clinical data to patient therapy.

The use of weekly 35-40 mg/m2 docetaxel, typically on a schedule of 6 weeks of therapy followed by a 2-week break, has produced response rates ranging from 33%-50% in patients with advanced breast cancer, the majority of whom have already received chemotherapy. These encouraging levels of response are seen across disease sites and in patients with prior anthracycline exposure. Importantly, the weekly administration of docetaxel allows prolonged treatment to a high cumulative dose: the weekly regimen is minimally myelotoxic, and neuropathy and other adverse events are infrequent.