Semimechanistic Clearance Models of Oncology Biotherapeutics and Impact of Study Design: Cetuximab as a Case Study.

This study aimed to explore the currently competing and new semimechanistic clearance models for monoclonal antibodies and the impact of clearance model misspecification on exposure metrics under different study designs exemplified for cetuximab. Six clearance models were investigated under four different study designs (sampling density and single/multiple-dose levels) using a rich data set from two cetuximab clinical trials (226 patients with metastatic colorectal cancer) and using the nonlinear mixed-effects modeling approach. A two-compartment model with parallel Michaelis-Menten and time-decreasing linear clearance adequately described the data, the latter being related to post-treatment response. With respect to bias in exposure metrics, the simplified time-varying linear clearance (CL) model was the best alternative. Time-variance of the linear CL component should be considered for biotherapeutics if response impacts pharmacokinetics. Rich sampling at steady-state was crucial for unbiased estimation of Michaelis-Menten elimination in case of the reference (parallel Michaelis-Menten and time-varying linear CL) model.

Versatile role of curcumin and its derivatives in lung cancer therapy.

Lung cancer is a main cause of death all over the world with a high incidence rate. Metastasis into neighboring and distant tissues as well as resistance of cancer cells to chemotherapy demand novel strategies in lung cancer therapy. Curcumin is a naturally occurring nutraceutical compound derived from Curcuma longa (turmeric) that has great pharmacological effects, such as anti-inflammatory, neuroprotective, and antidiabetic. The excellent antitumor activity of curcumin has led to its extensive application in the treatment of various cancers. In the present review, we describe the antitumor activity of curcumin against lung cancer. Curcumin affects different molecular pathways such as vascular endothelial growth factors, nuclear factor-κB (NF-κB), mammalian target of rapamycin, PI3/Akt, microRNAs, and long noncoding RNAs in treatment of lung cancer. Curcumin also can induce autophagy, apoptosis, and cell cycle arrest to reduce the viability and proliferation of lung cancer cells. Notably, curcumin supplementation sensitizes cancer cells to chemotherapy and enhances chemotherapy-mediated apoptosis. Curcumin can elevate the efficacy of radiotherapy in lung cancer therapy by targeting various signaling pathways, such as epidermal growth factor receptor and NF-κB. Curcumin-loaded nanocarriers enhance the bioavailability, cellular uptake, and antitumor activity of curcumin. The aforementioned effects are comprehensively discussed in the current review to further direct studies for applying curcumin in lung cancer therapy.

Clinically Relevant Cytochrome P450 3A4 Induction Mechanisms and Drug Screening in Three-Dimensional Spheroid Cultures of Primary Human Hepatocytes.

Cytochrome P450 (CYP) 3A4 induction is an important cause of drug-drug interactions, making early identification of drug candidates with CYP3A4 induction liability in drug development a prerequisite. Here, we present three-dimensional (3D) spheroid cultures of primary human hepatocytes (PHHs) as a novel CYP3A4 induction screening model. Screening of 25 drugs (12 known CYP3A4 inducers in vivo and 13 negative controls) at physiologically relevant concentrations revealed a 100% sensitivity and 100% specificity of the system. Three of the in vivo CYP3A4 inducers displayed much higher CYP3A4 induction capacity in 3D spheroid cultures as compared with in two-dimensional (2D) monolayer cultures. Among those, we identified AZD1208, a proviral integration site for Moloney murine leukemia virus (PIM) kinase inhibitor terminated in phase I of development due to unexpected CYP3A4 autoinduction, as a CYP3A4 inducer only active in 3D spheroids but not in 2D monolayer cultures. Gene knockdown experiments revealed that AZD1208 requires pregnane X receptor (PXR) to induce CYP3A4. Rifampicin requires solely PXR to induce CYP3A4 and CYP2B6, while phenobarbital-mediated induction of these CYPs did not show absolute dependency on either PXR or constitutive androstane receptor (CAR), suggesting its ability to switch nuclear receptor activation. Mechanistic studies into AZD1208 uncovered an involvement of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway in CYP3A4 induction that is sensitive to the culture format used, as revealed by its inhibition of ERK1/2 Tyrosine 204 phosphorylation and sensitivity to epidermal growth factor (EGF) pressure. In line, we also identified lapatinib, a dual epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) inhibitor, as another CYP3A4 inducer only active in 3D spheroid culture. Our findings offer insights into the pathways involved in CYP3A4 induction and suggest PHH spheroids for preclinical CYP3A4 induction screening.

Formononetin inhibits tumor growth by suppression of EGFR-Akt-Mcl-1 axis in non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) activating mutations play crucial roles in the tumorigenesis of human non-small cell lung cancer (NSCLC). The mechanism regarding how EGFR signaling regulates myeloid cell leukemia sequence 1 (Mcl-1) protein stability and ubiquitination remains undefined. METHODS: MTS assay was used for natural product library screening. The effect of formononetin (Formo) on NSCLC cells was determined by MTS assay and soft agar assay. Molecular modeling was performed to analyze the potential different binding modes between Formo and EGFR WT or mutants. Mcl-1 protein level and the inhibitory effect of Formo on EGFR signaling were examined by immunoblot, in vitro kinase assay, in vitro pulldown and ATP competition assays, co-immunoprecipitation assay, ubiquitination analysis, in vivo xenograft model, and immunohistochemical staining. RESULTS: Formo was identified as an EGFR inhibitor by a 98 commercially available natural product screening. Formo suppresses WT and mutant EGFR kinases activity in vitro, ex vivo, and in vivo. Molecular modeling indicates that Formo docks into the ATP-binding pocket of both WT and mutant EGFR. Formo inhibits EGFR-Akt signaling, which in turn activates GSK3ß and promotes Mcl-1 phosphorylation in NSCLC cells. Treatment with Formo enhances the interaction between Mcl-1 and SCFFbw7, which eventually promotes Mcl-1 ubiquitination and degradation. Depletion of either GSK3ß or SCFFbw7 compromised Formo-induced Mcl-1 downregulation. Finally, Formo inhibits the in vivo tumor growth in a xenograft mouse model. CONCLUSION: This study highlights the importance of promoting ubiquitination-dependent Mcl-1 turnover might be an alternative strategy to enhance the anti-tumor efficacy of EGFR-TKI.

Isoliquiritigenin Suppressed Esophageal Squamous Carcinoma Growth by Blocking EGFR Activation and Inducing Cell Cycle Arrest.

Isoliquiritigenin (ILQ) is a natural product isolated from licorice root which has served as traditional Chinese medicine for a long time. Recently, the antitumor effects of ILQ have been widely studied in various cancers, but the role and related mechanisms of ILQ in esophageal squamous carcinoma cells (ESCC) are still poorly understood. In our studies, ILQ showed profound antitumor activities in ESCC cells. In vitro, ILQ substantially inhibited cell proliferation and anchorage-independent growth in a panel of human ESCC cells. Mechanism studies showed that EGFR signaling pathway played an important role for ILQ to exert its antitumor activity in ESCC. Exposure to isoliquiritigenin substantially decreased EGF-induced EGFR activation and its downstream Akt and ERK1/2 signaling pathway. EGFR knockdown with shRNA in ESCC cell significantly reduced the sensitivity of cancer cells to ILQ. Moreover, it was found that ILQ had a significantly inhibitory effect on AP-1 family, the protein of Jun and Fos subfamilies was substantially downregulated, and the transcriptional activity of AP-1 family was dramatically suppressed by ILQ. By reducing the expression of cyclin D1, ESCC cells were induced G0/G1 arrest, and cell division was substantially blocked. Finally, the antitumor potency of ILQ was validated in xenograft models and the tumor growth was prominently restrained by ILQ. Briefly, our study showed that ILQ, or its analogue, appeared to be a promising new therapeutic agent for ESCC management.

Observational Study of Treatment Patterns in Patients with Epidermal Growth Factor Receptor (EGFR) Mutation-Positive Non-Small Cell Lung Cancer After First-Line EGFR-Tyrosine Kinase Inhibitors.

INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations are observed in approximately 15% of patients with non-small cell lung cancer (NSCLC) in the USA. Little is known about treatment patterns in EGFR mutation-positive NSCLC following progression on or after first-line (1L) treatment with first- or second-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs). Osimertinib, a third-generation EGFR-TKI, is a treatment option for patients with EGFR T790M-positive NSCLC following progression on 1L EGFR-TKIs. This study analyzed real-world treatment sequencing of EGFR-TKIs, EGFR T790M testing rates, and disposition of patients with EGFR mutations after 1L EGFR-TKI post-FDA approval of osimertinib in patients with EGFR mutation-positive NSCLC. METHODS: Adult patients with stage IV NSCLC and documented EGFR mutation-positive status were identified between December 1, 2015 and May 31, 2017 from the US Oncology Network iKnowMed™ electronic health record (EHR). Data were abstracted from the EHR database and supplemented by chart review. RESULTS: Of 308 patients, 302 (98%) received an EGFR-TKI overall, and 246 patients (80%) received a 1L EGFR-TKI. The most common 1L EGFR-TKI was erlotinib (66%); the remaining 1L regimens were predominantly combination chemotherapies with or without an EGFR-TKI. Only 80 patients (26%) received any 2L therapy. The most common EGFR-TKIs used as 2L monotherapy in patients who received 1L EGFR-TKI were afatinib and osimertinib (n = 7 for both). Among all patients treated with 1L EGFR-TKI (n = 246), 47 (19%) were tested for EGFR T790M [16 patients (34%) were positive], 48 (20%) remained on 1L EGFR-TKI, 29 (12%) received subsequent therapy, 38 (15%) had died on or after their 1L EGFR-TKI therapy, and 131 (53%) stopped their EGFR-TKI with no recorded evidence of having received subsequent therapy at follow-up end. CONCLUSION: Following 1L EGFR-TKI treatment, 19% of patients were tested for EGFR T790M, and most (69%) had no record of receiving any subsequent therapy.

Effect of Astragalus Polysaccharide on the Expression of VEGF and EGFR in Mice with Lewis Transplantable Lung Cancer.

The aim of this study was to determine the effect of Astragalus polysaccharide (APS) on the expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) in mice with Lewis transplantable lung cancer. It was an experimental study carried out from June 2017 to January 2018 at the College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China. Forty male SPF-level C57BL/6J mice were selected and inoculated with Lewis lung cancer cell suspension in the right axilla of the mice to establish a lung-cancer mouse model. The mice were randomly divided into a model control group and APS groups with high, middle and low dosages, respectively, 10 in each group. After inoculation of Lewis tumor cell suspension for 2 days, mice in the model control group were injected intraperitoneally with 50 mL/kg of 0.9% sodium chloride solution, whereas, mice in the APS groups with high, middle and low dosages were intraperitoneally injected with APS at 100, 50, 25 mg/kg, respectively. The research results showed that APS can effectively inhibit the growth and metastasis of Lewis lung cancer in mice, improve immune organ function, inhibit the protein expression of VEGF and EGFR in tumor tissues, and have a concentration-effect relationships.

Shikonin enhances sensitization of gefitinib against wild-type EGFR non-small cell lung cancer via inhibition PKM2/stat3/cyclinD1 signal pathway.

AIMS: Mutant EGFR Non-small cell lung cancer has benefit from gefitinib, but it has limited effect for wild-type EGFR tumors. Shikonin, a natural naphthoquinone isolated from a traditional Chinese medicine, the plant Lithospermum erythrorhizon (zicao), not only can inhibit the tumor growth, but also overcome cancer drug resistance. Our aim is to investigate whether shikonin can enhance antitumor effect of gefitinib in EGFR wild-type lung cancer cells in vitro and in vivo. MATERIALS AND METHODS: CCK-8 was used to determine the proliferation of EGFR wild-type non-small cell lung cancer. Apoptosis and cell cycle were detected by flow cytometry. PKM2, STAT3, p-STAT3 and cyclinD1 were detected by Western blot. A549 tumor model was established to observe the antitumor effect of shikonin combination with gefitinib in vivo. KEY FINDINGS: The results showed that combination of shikonin with gefitinib exhibited synergistic antitumor effect in vitro and in vivo. Its potential molecular mechanisms may be associated with inhibition of PKM2/STAT3/cyclinD1. SIGNIFICANCE: These results provide a promising therapeutic approach for the treatment of wild-type EGFR non-small cell lung cancer.

Enhanced anticancer effects of Scutellaria barbata D. Don in combination with traditional Chinese medicine components on non-small cell lung cancer cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Experience-based herbal medicine as a complementary to modern western medicine has triggered an array of studies in quest of novel anticancer drugs. Scutellaria barbata D. Don (SB) is commonly used to treat different types of cancers, but its molecular mechanism of action is not clearly understood. In this study, we attempted to elucidate the mode of action of a traditional Chinese medicine prescription with a total of 14 components, named Lian-Jia-San-Jie-Fang (LJSJF, in Chinese), where SB works as the "principle" against non-small cell lung cancer (NSCLC) cells. MATERIALS AND METHODS: Four different NSCLC cell lines (A549, H460, H1650, and H1975) were used. Cytotoxicity, in vitro tumorigenicity, gene expression, and protein expression were analyzed by MTT assay, soft agar assay, real-time PCR, and Western blots, respectively. RESULTS: Among the 14 components in LJSJF, SB was the only one to possess cytotoxic effects at its pharmacologically relevant doses. Additionally, we observed synergistically dose-dependent cytotoxic effects of SB in combination with other LJSJF components. After SB or LJSJF treatment, significant reductions in colony number and/or size were observed in A549 and H460; a notable dose-dependent decrease in EGFR was observed in A549, H460, and H1650; significant downregulation in EGFR and its downstream signaling targets mTOR and p38MAPK were also observed in A549 and H460; and p53 and p21 were significantly increased while survivin, cyclin D1, and MDM2 were significantly decreased in A549. Additionally, p53, p21, and Mettl7b were decreased, but p73 was increased in H460. Neither EGFR nor p53 was changed in H1975. Therefore, SB or LJSJF may induce cytotoxic effects by regulating multiple and/or distinct apoptotic pathways in different NSCLC cells. CONCLUSION: LJSJF exerts more pronounced cytotoxic effects against NSCLC cells than SB does by synergistically regulating the underlining molecular mechanisms including EGFR and/or p53 signaling pathways.

Image-based compound profiling reveals a dual inhibitor of tyrosine kinase and microtubule polymerization.

Small-molecule compounds are widely used as biological research tools and therapeutic drugs. Therefore, uncovering novel targets of these compounds should provide insights that are valuable in both basic and clinical studies. I developed a method for image-based compound profiling by quantitating the effects of compounds on signal transduction and vesicle trafficking of epidermal growth factor receptor (EGFR). Using six signal transduction molecules and two markers of vesicle trafficking, 570 image features were obtained and subjected to multivariate analysis. Fourteen compounds that affected EGFR or its pathways were classified into four clusters, based on their phenotypic features. Surprisingly, one EGFR inhibitor (CAS 879127-07-8) was classified into the same cluster as nocodazole, a microtubule depolymerizer. In fact, this compound directly depolymerized microtubules. These results indicate that CAS 879127-07-8 could be used as a chemical probe to investigate both the EGFR pathway and microtubule dynamics. The image-based multivariate analysis developed herein has potential as a powerful tool for discovering unexpected drug properties.

Oleanolic acid isolated from ethanolic extract of Phytolacca decandra induces apoptosis in A375 skin melanoma cells: drug-DNA interaction and signaling cascade.

OBJECTIVE: Oleanolic acid (OA) has been reported to have anticancer effects, but the extent of its cytotoxicity, its ability to interact with nuclear DNA, its action against skin melanoma, as well as the molecular mechanism of its action against cell proliferation and in support of cell death are still unexplored. This led us to examine the efficacy of OA, a bioactive compound isolated from Phytolacca decandra, on these issues in the present investigation. METHODS: Studies related to analyses of cell viability, drug-DNA interaction, cell proliferation, cell cycle and epidermal growth factor receptor (EGFR) activity were performed. To investigate whether cells undergo apoptosis, studies like fluorescence microscopy, poly (ADP-ribose) polymerase (PARP) degradation, annexin V-fluorescein isothiocyanate/propidium iodide assay, alteration in mitochondrial membrane potential and activity of some relevant signaling proteins were performed. RESULTS: OA displayed a minimal and negligible cytotoxic effect on normal HaCaT cells (skin keratinocytes) and peripheral blood mononuclear cells but by contrast it reduced A375 cell viability significantly. OA interacted with nuclear DNA quickly after exposure. It acted as an anti-proliferative agent. It suppressed EGFR activity. OA administration led the cells to mitochondria-dependent caspase 3-mediated apoptosis. CONCLUSION: OA interacts with cellular DNA, inhibits proliferation possibly through modulating EGFR activity and induces mitochondria-dependent caspase 3-mediated apoptosis in A375 cells which would qualify it as a potent anticancer agent.

Identification and optimization of new dual inhibitors of B-Raf and epidermal growth factor receptor kinases for overcoming resistance against vemurafenib.

Epidermal growth factor receptor (EGFR) amplification has been demonstrated to be critical for the inherent and/or acquired resistance against current B-Raf(V600E) inhibitor therapy for melanoma and colorectal cancer patients. We describe the discovery and structure-activity relationship study of a series of 1H-pyrazolo[3,4-b]pyridine-5-carboxamide analogues as novel dual inhibitors of EGFR and B-Raf(V600E) mutant. One of the most promising compounds, 6a, potently inhibited both of the kinases with IC50 values of 8.0 and 51 nM, respectively. The compound also strongly suppressed the proliferation of a panel of intrinsic and acquired resistant melanoma and/or colorectal cancer cells harboring overexpressed EGFR with submicromolar IC50 values. Further mechanism investigation revealed that 6a could sustainably inhibit the activation of the MAPK path way in the resistant SK-MEL-28 PR30 melanoma cancer cells and WiDr colorectal cancer cells with EGFR amplification. Our results support the hypothesis that the EGFR/B-Raf(V600E) dual inhibition might be a tractable strategy to overcome the intrinsic and acquired resistance of melanoma and/or colorectal cancers against the current B-Raf(V600E) inhibitor therapy.

Protective effects of N-acetylcysteine on acetic acid-induced colitis in a porcine model.

BACKGROUND: Ulcerative colitis is a chronic inflammatory disease and involves multiple etiological factors. Acetic acid (AA)-induced colitis is a reproducible and simple model, sharing many characteristics with human colitis. N-acetylcysteine (NAC) has been widely used as an antioxidant in vivo and in vitro. NAC can affect several signaling pathways involving in apoptosis, angiogenesis, cell growth and arrest, redox-regulated gene expression, and inflammatory response. Therefore, NAC may not only protect against the direct injurious effects of oxidants, but also beneficially alter inflammatory events in colitis. This study was conducted to investigate whether NAC could alleviate the AA-induced colitis in a porcine model. METHODS: Weaned piglets were used to investigate the effects of NAC on AA-induced colitis. Severity of colitis was evaluated by colon histomorphology measurements, histopathology scores, tissue myeloperoxidase activity, as well as concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon. The protective role of NAC was assessed by measurements of antioxidant status, growth modulator, cell apoptosis, and tight junction proteins. Abundances of caspase-3 and claudin-1 proteins in colonic mucosae were determined by the Western blot method. Epidermal growth factor receptor, amphiregulin, tumor necrosis factor-alpha (TNF-α), and toll-like receptor 4 (TLR4) mRNA levels in colonic mucosae were quantified using the real-time fluorescent quantitative PCR. RESULTS: Compared with the control group, AA treatment increased (P < 0.05) the histopathology scores, intraepithelial lymphocyte (IEL) numbers and density in the colon, myeloperoxidase activity, the concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon, while reducing (P < 0.05) goblet cell numbers and the protein/DNA ratio in the colonic mucosa. These adverse effects of AA were partially ameliorated (P < 0.05) by dietary supplementation with NAC. In addition, NAC prevented the AA-induced increase in caspase-3 protein, while stimulating claudin-1 protein expression in the colonic mucosa. Moreover, NAC enhanced mRNA levels for epidermal growth factor and amphiregulin in the colonic mucosa. CONCLUSION: Dietary supplementation with NAC can alleviate AA-induced colitis in a porcine model through regulating anti-oxidative responses, cell apoptosis, and EGF gene expression.

Screening active compounds acting on the epidermal growth factor receptor from Radix scutellariae via cell membrane chromatography online coupled with HPLC/MS.

Radix scutellariae is a traditional Chinese medicine (TCM) and has many pharmacological effects, including antiviral, antibacterial, antifungal, antipyretic, hypotensive, anti-inflammatory and anti-anaphylaxis effects. However, few studies have screened the active compounds in this complex product for tumor therapy. In this study, a two-dimensional online method was developed to screen the active compounds from Radix scutellariae acting on the epidermal growth factor receptor. The screening results showed that wogonin from Radix scutellariae was the targeted component which acted on epidermal growth factor receptor specificity. The in vitro inhibitory activity of wogonin on the viability of cells with high epidermal growth factor receptor expression was tested using the MTT assay. In the dosage range of 0.40-50.0 µM, inhibition of HEK293/EGFR by wogonin was 8.94 ± 0.2, 20.64 ± 5.10, 34.16 ± 5.90 and 69.03 ± 7.80 at the concentrations of 0.4 × 10(-6), 2 × 10(-6), 10 × 10(-6) and 50 × 10(-6) molL(-1), respectively. These results showed that wogonin inhibited the growth of cells with high epidermal growth factor receptor expression in a dose-dependent manner.

Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism.

Probiotic bacteria can potentially have beneficial effects on the clinical course of several intestinal disorders, but our understanding of probiotic action is limited. We have identified a probiotic bacteria-derived soluble protein, p40, from Lactobacillus rhamnosus GG (LGG), which prevents cytokine-induced apoptosis in intestinal epithelial cells. In the current study, we analyzed the mechanisms by which p40 regulates cellular responses in intestinal epithelial cells and p40's effects on experimental colitis using mouse models. We show that the recombinant p40 protein activated EGFR, leading to Akt activation. Activation of EGFR by p40 was required for inhibition of cytokine-induced apoptosis in intestinal epithelial cells in vitro and ex vivo. Furthermore, we developed a pectin/zein hydrogel bead system to specifically deliver p40 to the mouse colon, which activated EGFR in colon epithelial cells. Administration of p40-containing beads reduced intestinal epithelial apoptosis and disruption of barrier function in the colon epithelium in an EGFR-dependent manner, thereby preventing and treating DSS-induced intestinal injury and acute colitis. Furthermore, p40 activation of EGFR was required for ameliorating colon epithelial cell apoptosis and chronic inflammation in oxazolone-induced colitis. These data define what we believe to be a previously unrecognized mechanism of probiotic-derived soluble proteins in protecting the intestine from injury and inflammation.

From probiotics to therapeutics: another step forward?

Preclinical studies with probiotics continue to unravel mechanisms of cytoprotection and suggest that approaches utilizing microbial products as therapeutics in acute and chronic gastrointestinal disorders could be effective. However, clinical trials using these bacteria have thus far been inconsistent. In this issue of the JCI, Yan et al. describe a novel mechanism of cytoprotection by p40, a soluble product of Lactobacillus rhamnosus GG, mediated via EGFR. The efficacy of p40 in three models of chemically induced colitis indicates tremendous therapeutic potential, though this finding will need to be verified in human patients.

Antitumor activity of taspine by modulating the EGFR signaling pathway of Erk1/2 and Akt in vitro and in vivo.

EGFR, as a critical signaling pathway in many human tumors, has become an important target of cancer drug design. Taspine has shown meaningful angiogenesis activity in previous studies. This paper is to investigate the antitumor action of taspine by modulating the EGFR signaling pathway. The study determined the expression of key signaling molecules of EGFR (EGFR, Akt, p-Akt, Erk, and p-Erk) by Western blot and real-time PCR and analyzed their correlations with subsequent reactions. In addition, the cell proliferation, migration, and EGF production were examined by MTT, transwell system, and ELISA. The antitumor activity in vivo was carried out by xenograft in athymic mice. The results showed that taspine could inhibit A431 and Hek293/EGFR cell proliferation and A431 cell migration as well as EGF production. Compared to the negative control, EGFR, Akt, and phosphorylation of Akt were significantly inhibited by taspine treatment in A431 and HEK293/EGFR cells. Consistent with the inhibition of Akt activity, Erk1/2 and its phosphorylation were reduced. Moreover, taspine inhibited A431 xenograft tumor growth. These results suggest that EGFR activated by EGF and its downstream signaling pathways proteins could be downregulated by taspine in a dose-dependent manner. The antitumor mechanism of taspine through the EGFR pathway lies in the ability to inhibit A431 cell proliferation and migration by reducing EGF secretion. This occurs through the repression of EGFR which mediates not only MAPK (Erk1/2) but also Akt signals.

Integrating molecular diagnostics into anticancer drug discovery.

In the 1990s, the breast cancer drug trastuzumab (Herceptin; Genentech/Roche)--an antibody specific for human epidermal growth factor receptor 2 (HER2; also known as ERBB2)--was approved based on trials in which HER2 expression levels were used to select patients in clinical trials. This provided support for analogous efforts for drugs that target the epidermal growth factor receptor (EGFR). However, the development of these drugs, such as cetuximab (Erbitux; Bristol-Myers Squibb/Lilly) and gefitinib (Iressa; AstraZeneca), has revealed that EGFR expression is an insufficient and unreliable biomarker to select patients for EGFR-targeted therapies in both lung and colon cancer. Indeed, evidence on patient populations that are likely to respond to such therapies, on the basis of specific mutations in proteins of the targeted pathway, has only recently been clinically validated and incorporated into some of the drug labels. This article highlights lessons learned from the development of the first drugs targeting the EGFR family and discusses strategies to decrease the risk of failure in clinical development by more effectively integrating molecular diagnostics into anticancer drug discovery.

[Treatment and prevention of acute radiation dermatitis]. / Traitement et prévention des radiodermites aiguës.

Acute radiation dermatitis is a common side-effect of radiotherapy which often necessitates interruption of the therapy. Currently, there is no general consensus about its prevention or about the treatment of choice. The goal of this work was to focus on optimal methods to prevent and manage acute skin reactions related to radiation therapy and to determine if there are specific topical or oral agents for the prevention of this acute skin reaction. The prevention and the early treatment are the two focus points of the management of the acute radiation dermatitis.