pki-166 and Lung-Neoplasms

The epidermal growth factor receptor (EGFR) plays an important role in the carcinogenesis of many human malignancies and is therefore an attractive target against which anticancer therapy may be effective. At present, there are two ways in which this may be achieved clinically: antibodies against EGFR and inhibitors of the EGFR tyrosine kinase. This review describes presently approved agents cetuximab (monoclonal EGFR antibody), gefitinib and erlotinib (EGFR tyrosine kinase inhibitors) in detail. Efficacy data for these agents in various human malignancies is presented. Various other agents that are in the early stages of development at present have also been mentioned.

Topics: Administration, Oral; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cetuximab; Colorectal Neoplasms; Drug Delivery Systems; Drug Evaluation, Preclinical; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Humans; Lung Neoplasms; Panitumumab; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quinazolines; Randomized Controlled Trials as Topic

During the last five years there has been interest in developing non-cytotoxic, targeted cancer treatments. This phenomenon has occurred as a result of increased information regarding factors which regulate tumor proliferation, survival, angiogenesis, invasiveness, and metastatic potential. In non-small cell lung cancer many investigators have focused their attention on the epidermal growth factor receptor (EGFR) because this membrane protein, which has an extracellular ligand binding domain, as well as, tyrosine kinase activity on the intracellular portion of the molecule, is expressed in a relatively high proportion of non-small cell lung cancers. Gefitinib which was the first EGFR specific tyrosine kinase inhibitor to be extensively tested in non-small cell lung cancer has shown single agent activity in non-small cell lung cancer. Subsequently, erlotinib, another EGFR specific tyrosine inhibitor, has also demonstrated single agent activity in non-small cell lung cancer. Phase III trials of erlotinib alone or in combination with chemotherapy have been completed, and data are being analyzed. Several dual inhibitors of erb B1 and erb B2 (PKI 166, GW 572016, EKB 569) have been or are being tested in phase I trials. In addition, CI 1033, a pan-erb inhibitor, is also being tested in phase I studies. Diarrhea and rash have been the predominant side effects of these agents. Life threatening toxicity has been rare. Although the erb tyrosine kinase inhibitors are attrative agents to use in treating non-small cell lung cancer because of their relatively benign toxicity profile, more data are needed to define the role of these agents in non-small cell lung cancer.

Topics: Aminoquinolines; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; ErbB Receptors; Erlotinib Hydrochloride; Humans; Lapatinib; Lung Neoplasms; Organic Chemicals; Protein-Tyrosine Kinases; Pyrimidines; Pyrroles; Quinazolines; Treatment Outcome

Improved understanding of tumor biology has led to the identification of numerous growth factors that are involved in malignant transformation and tumor progression. Many of these factors induce cellular responses through receptors with intrinsic tyrosine kinase (TK) activity. Therefore, inhibiting receptor TK activity is a way to effectively block the tumorigenic effects that arise from these pathways. The HER family of TK receptors is overexpressed or dysregulated in many types of human cancer. As a result these receptors were identified as targets for cancer therapy. Several agents have been developed that reversibly, or irreversibly, inhibit one, two or all of the HER receptors. Tarceva and Iressa are HER1-TK inhibitors that are advanced in development. Clinical data show that these agents as monotherapy have antitumor activity in patients with various types of solid tumor and are well tolerated; encouraging data are also produced when Tarceva or Iressa are combined with chemotherapeutic agents. Other dual or pan-HER, reversible or irreversible, TK inhibitors are being investigated in phase I trials. Early data show that they are generally well tolerated and have provided evidence of antitumor activity. HER-TK inhibitors are exciting agents that are likely to have a substantial impact on the way we treat patients with cancer.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Enzyme Inhibitors; ErbB Receptors; Erlotinib Hydrochloride; Female; Gefitinib; Head and Neck Neoplasms; Humans; Lung Neoplasms; Morpholines; Ovarian Neoplasms; Protein-Tyrosine Kinases; Pyrimidines; Pyrroles; Quinazolines; Receptor, ErbB-2

The purpose is to evaluate whether inhibition of epidermal growth factor receptor (EGFR) activation by PKI166, an EGFR-tyrosine kinase inhibitor, affects growth of human lung cancer implanted orthotopically into the lungs of nude mice.. Lungs of mice were injected with NCI-H358 human bronchioloalveolar cancer cells. In three experiments, groups of mice (n = 10 per group) were randomized 7 days after tumor implantation to receive one of the following treatments: i.p. paclitaxel 100 or 200 microg (4 or 8 mg/kg) once per week, oral PKI166 100 or 200 mg/kg three times per week, paclitaxel plus PKI166, or i.p. saline and oral PKI166-vehicle (control) for 5 weeks. Mice were killed 6.5 to 8 weeks after tumor implantation. The experiments were repeated with PC14PE6 human lung adenocarcinoma cells to assess effect on survival.. Immunohistochemical analyses revealed the expression and phosphorylation of EGFR in the growing tumors. Treatment with PKI166 alone or in combination with paclitaxel diminished activation of EGFR on tumor cells, yet maximal therapeutic effect was observed in mice treated with paclitaxel alone. Activated mitogen-activated protein kinase and basic fibroblast growth factor expression were similar in all treatment groups. Survival in mice treated with the combination of paclitaxel and PKI166 was shorter than in those treated with paclitaxel alone.. Our results suggest that concurrent administration of EGFR-tyrosine kinase inhibitor and chemotherapy is equivalent and may indeed be inferior to chemotherapy alone, even if EGFR is functional and its phosphorylation effectively inhibited. Our data show that the interaction of EGFR-TKIs and chemotherapy is complex and suggest that other growth factors may activate the downstream signaling events.

Topics: Adenocarcinoma, Bronchiolo-Alveolar; Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; Drug Therapy, Combination; Enzyme Activation; Enzyme Inhibitors; ErbB Receptors; Fibroblast Growth Factor 2; Humans; Lung Neoplasms; Male; Mice; Mice, Nude; Mitogen-Activated Protein Kinases; Models, Animal; Paclitaxel; Phosphorylation; Pyrimidines; Pyrroles; Survival Rate