Outcomes of patients with advanced epithelial growth factor receptor mutant lung cancer treated with first-line osimertinib who would not have met the eligibility criteria for the FLAURA clinical trial.

OBJECTIVES: Osimertinib is largely used as first-line therapy for metastatic epithelial growth factor receptor (EGFR) mutant lung cancers based on the FLAURA clinical trial. Real-world patient outcomes often differ from clinical trial outcomes. This study evaluated the efficacy of first-line osimertinib in patients treated in British Columbia (BC), Canada. Furthermore, we compared the outcomes of patients who would and would not have been eligible for the original FLAURA trial. METHODS: Consecutive patients receiving first-line osimertinib for metastatic EGFR exon19 or L858R lung cancer were identified using the BC Cancer Pharmacy Database. Patient eligibility for the FLAURA clinical trial were retrospectively reviewed based on the following criteria: ECOG ≥ 2, symptomatic brain metastases or on steroids, hemoglobin < 90 g/L, platelets < 100x109/L, or a creatinine clearance < 50 mL/min. mOS was assessed for the entire population and compared between patients who would have been eligible and ineligible for FLAURA. RESULTS: From January 2020 to October 2021, 311 patients received first-line osimertinib; 44 % (137/311) were deemed FLAURA ineligible, predominantly due to low ECOG (n = 120). After a median follow-up of 26.5 months, the mOS for the entire cohort was 27.4 months (95 %CI 23.8-30.1). The mOS for ineligible patients was 18 months shorter than eligible patients (15.8 vs 34.2, p < 0.001). Ineligible patients had higher rates of de novo stage IV disease, higher rates of stage IVB disease, and more sites of disease than eligible patients. CONCLUSION: In this real-world population, nearly half of patients would have been ineligible for FLAURA. The mOS was one year shorter than reported in FLAURA. However, patients who would have been eligible for the FLAURA clinical trial had similar OS to patients enrolled in FLAURA. Trial ineligible patients had a higher burden of disease at baseline which may have led to inferior outcomes. Further research is needed to improve outcomes in these patients.

Transcriptional Profiling and Consensus Molecular Subtype Assignment to Understand Response and Resistance to Anti-Epidermal Growth Factor Receptor Therapy in Colorectal Cancer.

PURPOSE: Activating mutations in KRAS, NRAS, and BRAF are known to cause resistance to anti-epidermal growth factor receptor (EGFR) therapy; however, only approximately 40% of patients with colorectal cancer (CRC) with RASWT tumors respond to anti-EGFR treatment. We sought to discover novel biomarkers to predict response to anti-EGFR antibody treatment in CRC and to understand mechanisms of resistance to anti-EGFR therapy. MATERIALS AND METHODS: Transcriptomic profiles from three clinical and two preclinical cohorts treated with cetuximab were used to assign consensus molecular subtypes (CMS) to each sample and correlated with outcomes. RESULTS: Restricting to RASWT patients, we observed that CMS2 tumors (canonical subtype) had significantly higher response rates relative to other CMS when treated with cetuximab combination with doublet chemotherapy (Okita et al cohort: 92% disease control rate (DCR) for CMS2, chi-square P = .04; CALGB/SWOG 80405 cohort: 90% objective response rate (ORR) for CMS2, chi-square P < .001) and with single-agent cetuximab (68%, chi-square P = .01). CMS2 tumors showed best response among right-sided (ORR = 80%) and left-sided (ORR = 92%) tumors in the CALGB/SWOG 80405 cohort. CMS2 cells lines were most likely to be sensitive to cetuximab (60%) and CMS2 patient-derived xenograft had the highest DCR (84%). We found Myc, E2F, and mammalian target of rapamycin pathways were consistently upregulated in resistant samples (enrichment score >1, false discovery rate <0.25). Inhibitors of these pathways in resistant cell lines exhibited additive effects with cetuximab. CONCLUSION: These data suggest that CRC transcriptional profiles, when used to assign CMS, provide additional ability to predict response to anti-EGFR therapy relative to using tumor sidedness alone. Notably both right-sided and left-sided CMS2 tumors had excellent response, suggesting that anti-EGFR therapy be included as a treatment option for right-sided CMS2 tumors.

Clinical characterization of stomatitis cases with an epithelial growth factor receptor inhibitor in metastatic colorectal cancer patients: A study of 7 cases and literature review.

OBJECTIVE: The aim of this study was to report a case series of patients with metastatic colorectal cancer (mCRC) undergoing panitumumab-containing regimens affected by oral lesions and to review the current literature. STUDY DESIGN: Electronic medical records of mCRC patients referred to treat mouth sores during the treatment with the anti-epithelial growth factor receptor (EGFR)-panitumumab-were retrospectively reviewed. Patients' characterization, clinical profile of oral lesions, and management outcomes were documented. Additionally, modifications or discontinuation of the antineoplastic treatment as well as the occurrence of other adverse events (AEs) were analyzed. RESULTS: A total of 7 patients were included. The oral lesions appeared in a median time of 10 days (range 7-11 days) after the drug administration. The median reported pain score was 5 (range 1-9), causing feeding discomfort. Oral lesions with a marked aphthous-like appearance, among others, occurred in all cases and involved nonkeratinized mucosa more likely. At least 1 patient had dose reduction of the treatment and 1 patient needed discontinuation due to panitumumab-associated stomatitis. Dermatologic AEs were the most prevalent. Clinical improvement was obtained with topical corticosteroid therapy and/or photobiomodulation. CONCLUSIONS: In summary, panitumumab-containing regimens were associated with a particular pattern of oral lesions consistent with stomatitis. This event may eventually affect the tolerability of the treatment in patients with mCRC.

Middle East and North Africa Registry to Characterize Rate of RAS Testing Status in Newly Diagnosed Patients with Metastatic Colorectal Cancer.

BACKGROUND: Rat sarcoma virus mutational status guides first-line treatment in metastatic colorectal cancer. This study was a multi center, multi-country ambispective, observational study in the Middle East and North Africa assessing regional rat sarcoma virus testing practices in newly diagnosed patients. METHODS: The retrospective arm (2011-2014) included adults with metastatic colorectal cancer who had initiated first-line therapy with ≥1 post-baseline visit and survival data. The prospective arm (2014-2019) enrolled newly diagnosed patients with histologically proven metastatic colorectal cancer with ≥1 measurable lesion per Response Evaluation Criteria in Solid Tumors, and tissue availability for biomarker analysis. Data look-back and follow-up were 2 years; the rate of RAS mutation was evaluated. RESULTS: RAS testing was ordered for patients in retrospective (326/417) and prospective (407/500) studies. In the former, testing was typically prescribed after first-line treatment initiation, significantly more in patients with stage IV disease (P < .005), resulting in the addition of targeted therapy (41.8% anti-epidermal growth factor receptor, 30.2% anti-vascular endothelial growth factor) in wild-type metastatic colorectal cancer, and significantly impacted the treatment of left-sided tumors (P = .037). In the latter, 58.4% were RAS wild-type; 41.6% were RAS mutant. Non-prescription of RAS testing was attributed to test unavailability, financial, or medical rea sons; predictors of testing prescription were older age, primary tumor in ascending colon, and high tumor grade. RAS status knowledge resulted in the addition of anti-vascular endothelial growth factor (20.4%) or anti-epidermal growth factor receptor therapy (21.2%). CONCLUSION: Before 2014, RAS testing in patients with colorectal cancer in the Middle East and North Africa was often performed after first-line treatment. Testing is more routine in newly diagnosed patients, potentially shifting early treatment patterns.

[A Case of Advanced Recurrent Rectal Cancer Successfully Treated by Rechallenge Therapy with an Anti-Epidermal Growth Factor Receptor(EGFR)Drug].

The patient was a 75-year-old man who had undergone potentially curative surgery for Stage Ⅲb rectal cancer followed by resection of liver metastases. Two years after the resection of liver metastases, lung and remnant liver metastases were found. He received chemotherapy for unresectable metastatic tumors. Based on the findings of molecular and pathological examinations(RAS: wild type; BRAF: wild type; MSI: negative; HER2: negative), the following chemotherapy regimens were administered: first-line, FOLFIRI plus panitumumab(PANI); second-line, mFOLFOX6; third-line, trifluridine/tipiracil; fourth- line, regorafenib. After fourth-line treatment, he was judged to have disease progression due to the increase in his lung and liver metastases and the elevation of tumor markers. All standard regimens were refractory, but the Eastern Cooperative Oncology Group performance status was zero and a liquid biopsy for RAS still showed wild type. Therefore, rechallenge therapy with anti-epidermal growth factor receptor(EGFR)drugs, cetuximab(CET)and irinotecan(IRI), was administered 13 months after the final course of FOLFIRI plus PANI treatment. After 4 courses of CET plus IRI, the size of the 2 metastatic tumors markedly decreased and his tumor marker levels normalized.

Prevention of Acne-Like Eruption Caused by Panitumumab Treatment through Oral Administration of Non-steroidal Anti-inflammatory Drugs.

Acne-like eruption caused by anti-epidermal growth factor receptor (EGFR) antibodies such as panitumumab reduces treatment adherence and patient QOL; an alternative therapy is desired. Meanwhile, the usefulness of oral Non-steroidal Anti-inflammatory Drugs (NSAIDs) for acne-like eruptions caused by low-molecular-weight EGFR inhibitors such as erlotinib has been reported in the treatment of lung cancer. This study aimed to investigate whether the combined use of oral NSAIDs and panitumumab for colorectal cancer patients helps prevent acne-like eruption. We retrospectively investigated 167 colorectal cancer patients who had been treated with panitumumab for three cycles or more. The observation period was set from the start of panitumumab treatment to the end of three cycles. Within this period, the incidence and severity of acne-like eruptions were compared. A total of 59 and 108 patients were in the NSAIDs use and non-use groups, respectively, showing differences in the incidence of acne-like eruption rates (78.0 vs. 90.7%, respectively; p = 0.033). In the use group, eruption severity grades 0, 1, 2, and 3 were observed in 13, 33, 13, and 0 patients, respectively; the corresponding values in the non-use group were 10, 60, 36, and 2, respectively (p = 0.007). Oral NSAIDs may help prevent acne-like eruptions caused by panitumumab.

The Clinical Effect of a Combination of Mouse Nerve Growth Factor and Methylcobalamin to Treat Lumbar Disc Herniation with Foot Drop: A Retrospective Cohort Study.

OBJECTIVE: To investigate the clinical effect of mouse nerve growth factor (mNGF) and methylcobalamin (MeCbl) for the treatment of lumbar disk herniation (LDH) with foot drop. METHODS: A total of 46 patients suffering from LDH with foot drop who underwent transforaminal lumbar interbody fusion (TLIF) surgery in our department from January 2015 to December 2017 were retrospectively analyzed. We divided these patients into two groups according to the different postoperative treatment which independently selected by patients after signing informed consent form: one group of 25 patients was treated with MeCbl alone (Group MeCbl), the other group of 21 patients was treated with a combination of mNGF and MeCbl (Group MeCbl+mNGF). Patient demographics, the visual analogue scale (VAS) scores, sensory and muscular strength improvement statistics at 1 week, 4 weeks, 12 weeks, and 12 months postoperatively were recorded. Motor/sensory deficits, sciatica and overall neurological outcome after treatment of MeCbl alone and combination of mNGF and MeCbl were retrospectively analyzed. RESULTS: The follow-up ranged between 12 and 42 months (mean 20.8 months). There were no significant differences between these two groups of patients with respect to sex ratio, age, smoking, diabetes, disease course, section of protruding disc(s), muscular strength of foot dorsiflexion or preoperative visual analogue scale (VAS) score (P > 0.05). The VAS scores of Group MeCbl+mNGF were significantly lower than Group MeCbl at 1 week, 4 weeks, 12 weeks, and 12 months postoperatively (4.32 ± 0.75 vs 5.25 ± 0.79,2.65 ± 0.48 vs 3.42 ± 0.52, 1.72 ± 0.36 vs 2.45 ± 0.39, 1.12 ± 0.22 vs 1.52 ± 0.24, P < 0.05). The effective rates of sensory improvement were significantly higher in Group MeCbl+mNGF compared with Group MeCbl at 12-week/12-month follow-up time point (90.48% vs 52.00%,95.24% vs 68.00%, P < 0.05). The effective rate of muscular strength improvement of the two groups did not differ significantly at 1 week after surgery but exhibited statistically significant differences at subsequent time points (61.90% vs 32.00%, 76.19% vs 44.00%, 80.95% vs 48.00%, P < 0.05). CONCLUSIONS: Application of mNGF had clinical effects on promoting the recovery of neurological function in patients suffering from LDH with foot drop.

Efecto reno-protector y reno-reparador del Factor de Crecimiento Epidérmico en biomodelo de Insuficiencia Renal Crónica / Reno-protective and reno-restorative effect of the Epidermal Growth Factor in biomodel of Chronic Renal Failure

Introducción: La Enfermedad Renal es un problema de salud mundial. El Factor de Crecimiento Epidérmico actúa como citoprotector y trófico reparador. Objetivo: Evaluar el efecto reno-protector y reno-reparador del Factor de Crecimiento Epidérmico en biomodelo de Insuficiencia Renal Crónica. Material y Métodos: Se estudiaron 120 ratas, Wistar, en 6 grupos: Control Negativo y positivo, Solución Salina Dosis Única y Múltiple, Factor de Crecimiento Epidérmico Dosis Única y Múltiple. Se aplicó para efecto reno-protector dosis única antes del daño, y para el reno-reparador dosis múltiples posterior al daño, a razón de 100 µg/kg de peso. Resultados: La creatinina, urea y ácido úrico disminuyeron significativamente en los grupos experimentales, con mayor disminución para el grupo experimental dosis única, por lo que el efecto reno-protector fue mayor que el reno-reparador para los esquemas de tratamiento utilizados. Conclusiones: El Factor de Crecimiento Epidérmico mostró efecto reno-protector y reno-reparador al disminuir las variables hematológicas de daño renal(AU)

Introduction: Kidney disease is a world health problem. Epidermic Growth Factor acts as cyto-protector, and trophic restorative. Objective: To assess the reno-protective and reno-restorative effect of the Epidermal Growth Factor in biomodel of Chronic Renal Failure. Material and Methods: 120 Wistar rats were studied in 6 groups: Negative and Positive Control, Saline Solution Single-Dose and Multiple-Dose, Epidermal Growth Factor Single-Dose and Multiple-Dose. A single dose was applied before the damage for the reno-protective effect, and multiple doses after the damage for the reno-restorative effect, at a rate of 100 µg/kg of weight. Results: Creatinine, urea, and uric acid diminished significantly in the experimental groups, with a higher decrease for experimental group with single dose; therefore, the reno-protective effect was higher than reno-restorative one for the treatment patterns used. Conclusions: Epidermal Growth Factor showed reno-protective and reno-restorative effect by diminishing the hematological variables in kidney damage(AU)

Nonsmall cell lung cancer therapy: insight into multitargeted small-molecule growth factor receptor inhibitors.

To date, lung cancer is the leading cause of cancer-related death worldwide, among which nonsmall cell lung cancer (NSCLC) comprises about 85%. Taking into account the side effects of surgery, radiation, platinum-based doublet chemotherapy, and the growth self-sufficiency characteristic of cancer cells, drugs have been discovered toward growth factor receptor (GFR) to treat NSCLC. As expected, these drugs provide a greater benefit. To increase the efficacy of such growth factor receptor tyrosine kinase inhibitors (RTKIs), coinhibition of GFR signaling pathways and combination of inhibitors along with radiation or chemotherapy have drew intense insight. Although clinical trials about single-agent RTKIs or their combination strategies suggest their increase potency against cancer, they are not beyond adverse effects, and sometimes the effects are more deadly than chemotherapy. Nevertheless the hope for RTKIs may be proved true by further researches and digging deep into cancer therapeutics.

Novel therapeutics in colorectal cancer.

Colorectal cancer is an excellent tumor model for evaluating novel therapeutic strategies. Development of a mechanistic understanding of how this cancer develops, spreads, and grows allows a tailored approach to all stages of treatment: prevention, adjuvant treatment, and therapy of advanced disease. We focus on therapy in the advanced disease setting, although progress in this area could lend itself to treatment of early or premalignant disease. In the last 20 years, information has been generated about the intracellular pathways of tumor formation, invasion, and metastasis. As a result, specific molecular processes have been targeted for therapeutic intervention, including cell surface growth factor receptors, proliferation signaling, cell cycling, apo-ptosis, angiogenesis, and matrix metalloproteinases. We review the scientific rationale for recently developed novel therapeutics in colorectal cancer, and the results of clinical trials to date. We also suggest appropriate clinical settings for specific targets and outline future directions of research.

Future therapies in hormone-refractory prostate cancer.

Hormone-refractory prostate cancer (HRPC) remains true to its name: it is largely refractory to attempts to delay its progression. Although the number of men presenting with metastatic prostate cancer has decreased significantly over the last several years, the death rate for those men is essentially unchanged. To alter the currently inevitable progression of HRPC to death, new targets and new therapies are needed. This article reviews investigational therapies directed against standard targets (eg, the hypothalamic-pituitary-gonadal axis) as well as novel targets (eg, the endothelin axis).

Novel approaches for targeted cancer therapy.

The clinical use of chemotherapeutic agents against malignant tumors is successful in many cases but suffers from major drawbacks. One drawback is lack of selectivity, which leads to severe side effects and limited efficacy; and another is the emergence/selection of drug-resistance. To limit non-specific toxicity and to improve the efficiency of cancer therapy, "tumor markers", which are proteins generally overexpressed on the surface of tumor cells, can be selectively targeted. Growth factor receptors are one of the most extensively studied tumor markers. The implication of growth factor receptors in the pathogenesis and evolution of cancer has clearly been established and therefore, provides a rationale for therapeutic intervention. The targeting of cytotoxic substances to tumor markers with "magic bullets" is an old idea that raised high expectations but also disappointment. Over the past decade, newly gained understanding of mechanisms for targeted therapy have brought new hopes. Pharmacological agents that selectively target and block the action of growth factors and their receptors have been attempted, such as monoclonal antibodies (mAbs) (whole molecule or fragments), bispecific antibodies, mAbs conjugated to drugs, toxins or radioisotopes, small peptidic and peptidomimetic molecules in free form or conjugated to drugs, anti-sense oligonucleotides, immunoliposomes-encapsulated drugs, and small molecule inhibitors. This review will focus on current developments of selective targeting and bypassing drug resistance in the management of growth factor receptor-overexpressing tumors.

VEGF-TRAP(R1R2) suppresses choroidal neovascularization and VEGF-induced breakdown of the blood-retinal barrier.

Vascular endothelial growth factor (VEGF) plays a central role in the development of retinal neovascularization and diabetic macular edema. There is also evidence suggesting that VEGF is an important stimulator for choroidal neovascularization. In this study, we investigated the effect of a specific inhibitor of VEGF, VEGF-TRAP(R1R2), in models for these disease processes. VEGF-TRAP(R1R2) is a fusion protein, which combines ligand binding elements taken from the extracellular domains of VEGF receptors 1 and 2 fused to the Fc portion of IgG1. Subcutaneous injections or a single intravitreous injection of VEGF-TRAP(R1R2) strongly suppressed choroidal neovascularization in mice with laser-induced rupture of Bruch's membrane. Subcutaneous injection of VEGF-TRAP(R1R2) also significantly inhibited subretinal neovascularization in transgenic mice that express VEGF in photoreceptors. In two models of VEGF-induced breakdown of the blood-retinal barrier (BRB), one in which recombinant VEGF is injected into the vitreous cavity and one in which VEGF expression is induced in the retina in transgenic mice, VEGF-TRAP(R1R2) significantly reduced breakdown of the BRB. These data confirm that VEGF is a critical stimulus for the development of choroidal neovascularization and indicate that VEGF-TRAP(R1R2) may provide a new agent for consideration for treatment of patients with choroidal neovascularization and diabetic macular edema.

[Impact of extracellular gene of VEGF receptor KDR on growth of human bladder carcinoma in nude rats].

OBJECTIVE: To investigate the anti-angiogenesis activity of the extracellular domain of vascular endothelial growth factor (VEGF) receptor KDR. METHODS: The eukaryotic expression plasmid pcDNA3.1/KDR(n7) of the extracellular domain of KDR was transfected into the human bladder carcinoma EJ cells by lipofactamin technology. Cellular clone that stably expressed the target protein was obtained by G418 screening. The cellular clone that expressed the target protein specifically combined with VEGF was obtained by solid-phase binding assay. The positive cellular clone was identified by RT-PCR. RESULTS: The rKDR(n7) expressed by EJ cells can inhibit the angiogenesis in egg CAM. The EJ cell strain significantly inhibits the growth and angiogenesis of human bladder carcinoma in nude rat. The microvascular density in the experimental group was 12 +/- 4, significantly lower than that in hte negative control group (62 +/- 11). CONCLUSION: Inhibition of the VEGF/KDR signal transmission channel can inhibit the angiogenesis in tumor, thus delaying its growth.

De novo expression of vascular endothelial growth factor in human pancreatic cancer: evidence for an autocrine mitogenic loop.

BACKGROUND & AIMS: The role of vascular endothelial growth factor (VEGF) and its receptors in tumor angiogenesis has been well established. We analyzed the expression pattern and biologic significance of VEGF and its receptors in human pancreatic cancer. METHODS: VEGF, KDR/flk-1, and flt-1 expression were examined by immunohistochemistry, in situ hybridization, reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and receptor phosphorylation. VEGF-stimulated mitogenesis was investigated by mitogen-activated protein kinase (MAPK) phosphorylation, transactivation of a c-fos promoter reporter construct, DNA synthesis assays, and stable transfection of a dominant-negative flk-1 complementary DNA (cDNA) construct. RESULTS: Compared with normal pancreas and chronic pancreatitis, VEGF and its receptors were overexpressed in pancreatic cancer. KDR and flt-1 were detected not only in endothelial cells but also in tumor cells. VEGF expression was observed in all human pancreatic tumor cell lines examined, and the KDR/flk-1 and flt-1 receptor was detected in 2 cell lines. VEGF treatment results in phosphorylation of MAPKs, transactivation of a c-fos promoter construct, and growth stimulation in KDR/flk-1-expressing cell lines, which could be blocked by VEGF antagonists. Furthermore, stable transfection of a dominant-negative flk-1 cDNA significantly inhibited tumor cell growth. CONCLUSIONS: These results not only support the important role of the VEGF/VEGF receptor system in pancreatic tumor biology but also suggest the existence of an autocrine/paracrine mitogenic loop for pancreatic cancer cells.

Treatment with soluble VEGF receptor reduces disease severity in murine collagen-induced arthritis.

Maintenance of the invasive pannus in rheumatoid arthritis is an integral part of disease progression. The synovial vasculature plays an important role in the delivery of nutrients, oxygen, and inflammatory cells to the synovium. Vascular endothelial growth factor (VEGF), an endothelial mitogen expressed by cells within the synovial membrane, is thought to contribute to the formation of synovial blood vessels. Our objective in this study was to measure the kinetics of VEGF production in a murine model of collagen-induced arthritis and to determine whether VEGF blockade reduces disease progression. Synovial cells isolated from the knee joints of naive or sham-immunized mice, or from mice immunized with collagen but without arthritis, released little or no detectable VEGF. Onset of arthritis was associated with expression of VEGF mRNA and protein. The levels of VEGF secreted by synovial cells isolated from the joints of mice with severe arthritis were significantly higher than from mice with mild disease. To block VEGF activity, animals were treated after arthritis onset with a soluble form of the Flt-1 VEGF receptor (sFlt), which was polyethylene glycol (PEG)-linked to increase its in vivo half-life. Treatment of arthritic mice with sFlt-PEG significantly reduced both clinical score and paw swelling, compared with untreated or control-treated (heat-denatured sFlt-PEG) animals. There was also significantly less joint inflammation and reduced bone and cartilage destruction in sFlt-PEG-treated animals, as assessed by histology. Our data demonstrate that, in collagen-induced arthritis, expression of the potent angiogenic cytokine VEGF correlates with disease severity. Furthermore, specific blockade of VEGF activity results in attenuation of arthritis in both macroscopic and microscopic parameters. These observations indicate that blood vessel formation is integral to the development of arthritis and that blockade of VEGF activity might be of therapeutic benefit in rheumatoid arthritis.

Suppression of tumor angiogenesis and growth by gene transfer of a soluble form of vascular endothelial growth factor receptor into a remote organ.

Antiangiogenic therapy shows promise as a strategy for cancer treatment. We constructed an adenovirus (AdVEGF-ExR) expressing the entire extracellular domain of the human vascular endothelial growth factor (VEGF) receptor (flt-1) fused to the Fc portion of human IgG. The soluble receptor secreted from AdVEGF-ExR-infected cells bound to VEGF and inhibited VEGF-induced DNA synthesis in endothelial cells. When human lung cancer cell line H157, which produces not only VEGF but also fibroblast growth factor 2 and interleukin 8 at substantial levels, was infected with AdVEGF-ExR, cell growth in vitro was not affected. However, when H157 cells infected with AdVEGF-ExR were injected s.c. into nude mice, tumor formation stopped on the 10th day after reaching a certain size (about 100 mm3), and tumor size declined gradually thereafter. When AdVEGF-ExR was injected into skeletal muscle and uninfected H157 cells were injected s.c., the soluble receptor was detectable in the circulating blood for 3 weeks, tumor growth ceased after 10 days, and tumor size declined thereafter. Histological examination revealed that intratumor angiogenesis was markedly suppressed, and apoptosis was enhanced. Using the same experimental protocol, a significant suppression of tumor growth was also seen in four of five other lung cancer cell lines, some of which secreted VEGF at nominal levels, at least under normoxic conditions in vitro. Our results demonstrate that adenovirus-mediated expression of a soluble VEGF receptor in a remote organ could inhibit tumor angiogenesis and enhance apoptosis and thereby suppress tumor growth in vivo. Adenovirus-mediated overexpression of a soluble VEGF receptor in a remote organ may have the potential to be a feasible and effective strategy for cancer treatment.

Principles of treatment of malignant gliomas in adults: an overview.

The cornerstone of conventional treatments of malignant gliomas in adults has been surgical debulking, radiation therapy and chemotherapy. Almost always a combination of these treatments is used. With these conventional treatments the outcome, as measured by survival and quality of life, has remained universally dismal. Novel treatments, which are at different stages of laboratory and clinical trials, may offer a ray of hope for treatment of malignant gliomas. Development of these methods are directly related to the discoveries, over the past two decades, of cellular and molecular mechanisms involved in the genesis of brain tumors. Understanding of the mechanisms of tumor genesis may open new avenues of effective treatments for this devastating cancer.