epidermal-growth-factor and tipifarnib

The aims of chemoprevention in lung cancer are to prevent the appearance of disease (primary prevention) and to stop or reverse the progression of premalignant lesions (secondary prevention). Until recently, there was little hope that these goals could be attained. However, the results achieved with tamoxifen in the prevention of breast cancer, and the emergence of new therapies specifically targeted to molecules involved in the pathogenesis of lung cancer have set the stage for investigation of these agents for chemoprevention of lung cancer. Two of these new molecular targeted agents are gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase activity, and tipifarnib (R115777, Zarnestra ), an inhibitor of the farnesyltransferase enzyme, which is required for the proper localization and function of the ras oncogene. Tumor responses and disease stabilization have been achieved with both agents in clinical trials. In the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and IDEAL-2 phase II trials, gefitinib was demonstrated to be effective for disease control in patients with advanced non-small-cell lung cancer. The SPORE (Specialized Program of Research Excellence) Trials of Lung Cancer Prevention (STOP) are 2 parallel studies that will investigate the potential effectiveness of gefitinib and tipifarnib in preventing the appearance and progression of premalignant lesions in former or current smokers with a history of smoking-related cancer. These trials should provide information not only about the potential role of gefitinib and tipifarnib in lung cancer chemoprevention, but also about the molecular changes that underlie tumorigenesis and that may serve as markers of disease progression. The STOP trial objectives are to evaluate the effect of gefitinib and tipifarnib on histologic and biologic parameters in patients with evidence of sputum atypia, to evaluate various parameters as potential predictors of the effectiveness of these agents, and to evaluate the tolerability of these agents over a 6-month course of treatment. Histologic response, defined as prevention of appearance or progression of premalignant lesions, is the primary endpoint of these trials. New targeted molecular therapies such as gefitinib and tipifarnib may offer the opportunity to make chemoprevention a viable treatment modality in lung cancer as well as in other human solid tumors.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Chemoprevention; Clinical Trials as Topic; Disease Progression; Epidermal Growth Factor; Gefitinib; Humans; Lung Neoplasms; Precancerous Conditions; Protein-Tyrosine Kinases; Quinazolines; Quinolones

Topics: Alkyl and Aryl Transferases; Angiogenesis Inhibitors; Antineoplastic Agents; Benzamides; Benzodiazepines; Clinical Trials as Topic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Endothelial Growth Factors; Enzyme Inhibitors; Epidermal Growth Factor; ErbB Receptors; Erlotinib Hydrochloride; Farnesyltranstransferase; Gefitinib; Humans; Imatinib Mesylate; Imidazoles; Intercellular Signaling Peptides and Proteins; Lung Neoplasms; Lymphokines; Metalloendopeptidases; Multicenter Studies as Topic; Piperazines; Polyisoprenyl Phosphates; Protein-Tyrosine Kinases; Pyrimidines; Quinazolines; Quinolones; Randomized Controlled Trials as Topic; Receptor Protein-Tyrosine Kinases; Sesquiterpenes; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The goal of this study was to develop a 99mTc labelled human epidermal growth factor (hEGF) for the in-vivo prediction of cancer cell response to farnesyltransferase inhibitor (FTI) therapy. This is based on the observation that internalization of EGF receptors is inhibited by FTIs.. We describe the radiolabelling of 99mTc-hEGF using the hydrazinonicotinamide (HYNIC) linker. Binding characteristics of 99mTc-HYNIC-hEGF to the EGF receptor are explored using an in-vitro binding assay. Biodistribution data of the compound in mice and tumour uptake in LoVo tumour bearing athymic mice before and after farnesyltransferase inhibitor therapy are presented.. No colloid formation was observed. Binding parameters and LoVo tumour uptake of 99mTc-HYNIC-hEGF did not differ significantly from directly labelled 123I-hEGF values. However, the biodistribution data of the 99mTc-HYNIC-hEGF showed higher uptake in liver and intestines and decreased stomach uptake compared to its 123I analogue. Eight hours after farnesyltransferase inhibitor therapy with R115777, LoVo tumour uptake of 99mTc-HYNIC-hEGF decreased significantly, as shown using planar gamma scintigraphy (the ratio tumour vs. thigh dropped from 2.54+/-0.83 to 0.99+/-0.18). These data confirm the results obtained using 123I-hEGF.. These data suggest that 99mTc-HYNIC-hEGF is a promising and selective new radiotracer for in-vivo monitoring of the EGF receptor with SPECT. Moreover, 99mTc-HYNIC-hEGF is a possible tool for early therapy response prediction of farnesyltransferase inhibitors.

Topics: Alkyl and Aryl Transferases; Animals; Biomarkers, Tumor; Cell Line, Tumor; Colonic Neoplasms; Epidermal Growth Factor; ErbB Receptors; Farnesyltranstransferase; Humans; Male; Metabolic Clearance Rate; Mice; Organ Specificity; Organotechnetium Compounds; Quinolones; Radionuclide Imaging; Radiopharmaceuticals; Tissue Distribution; Treatment Outcome

The radiolabelled growth factor [(123/125)I] I-hEGF is evaluated in vitro and in vivo to monitor the acute effects on the EGFR of R115777, a farnesyl transferase inhibitor (FTI). Upregulation of the EGFR after incubation with R115777 correlated linearly with FTI induced acute growth inhibition. Receptor mediated [125I] I-hEGF internalization decreased following R115777 treatment. Preliminary data suggest that the net in vivo effect is a decrease of [123I] I-hEGF uptake in the tumour. These findings suggest the possible use of radioiodinated hEGF as a radiodiagnosticum to investigate EGFR status changes as a predictor for eventual FTI chemotherapy outcome in vivo.

Topics: Alkyl and Aryl Transferases; Animals; Cell Line; Enzyme Inhibitors; Epidermal Growth Factor; ErbB Receptors; Farnesyltranstransferase; Humans; Iodine Radioisotopes; Magnetic Resonance Imaging; Male; Mice; Mice, Nude; Neoplasm Transplantation; Quinolones; Radiopharmaceuticals; Regression Analysis; Tissue Distribution

Pamidronate (PAM) and zoledronic acid (ZOL) are aminobisphosphonates (BPs) able to affect the isoprenylation of intracellular small G proteins. We have investigated the antitumor activity of BPs and R115777 farnesyl transferase inhibitor (FTI) against epidermoid cancer cells. In human epidermoid head and neck KB and lung H1355 cancer cells, 48 h exposure to PAM and ZOL induced growth inhibition (IC(50) 25 and 10 microM, respectively) and apoptosis and abolished the proliferative and antiapoptotic stimuli induced by epidermal growth factor (EGF). In these experimental conditions, ZOL induced apoptosis through the activation of caspase 3 and a clear fragmentation of PARP was also demonstrated. A strong decrease of basal ras activity and an antagonism on its stimulation by EGF was recorded in the tumor cells exposed to BPs. These effects were paralleled by impaired activation of the survival enzymes extracellular signal regulated kinase 1 and 2 (Erk-1/2) and Akt that were not restored by EGF. Conversely, farnesol induced a recovery of ras activity and antagonized the proapoptotic effects induced by BPs. The combined treatment with BPs and R115777 resulted in a strong synergism both in growth inhibition and apoptosis in KB and H1355 cells. The synergistic activity between the drugs allowed BPs to produce tumor cell growth inhibition and apoptosis at in vivo achievable concentrations (0.1 micromolar for both drugs). Moreover, the combination was highly effective in the inhibition of ras, Erk and Akt activity, while farnesol again antagonized these effects. In conclusion, the combination of BPs and FTI leads to enhanced antitumor activity at clinically achievable drug concentrations that resides in the inhibition of farnesylation-dependent survival pathways and warrants further studies for clinical translation.

Topics: Alkyl and Aryl Transferases; Apoptosis; Caspases; Cell Division; Diphosphonates; Drug Synergism; Enzyme Inhibitors; Epidermal Growth Factor; Farnesyltranstransferase; Humans; Imidazoles; KB Cells; Mitogen-Activated Protein Kinases; Pamidronate; Protein Prenylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Quinolones; Zoledronic Acid