5-Aminolevulinic acid enhances cell death under thermal stress in certain cancer cell lines.

5-aminolevulinic acid (5-ALA) is contained in all organisms and a starting substrate for heme biosynthesis. Since administration of 5-ALA specifically leads cancer cells to accumulate protoporphyrin IX (PpIX), a potent photosensitizer, we tested if 5-ALA also serves as a thermosensitizer. 5-ALA enhanced heat-induced cell death of cancer cell lines such as HepG2, Caco-2, and Kato III, but not other cancer cell lines including U2-OS and normal cell lines including WI-38. Those 5-ALA-sensitive cancer cells, but neither U2-OS nor WI-38, accumulated intracellular PpIX and exhibited an increased reactive oxygen species (ROS) generation under thermal stress with 5-ALA treatment. In addition, blocking the PpIX-exporting transporter ABCG2 in U2-OS and WI-38 cells enhanced their cell death under thermal stress with 5-ALA. Finally, a ROS scavenger compromised the cell death enhancement by 5-ALA. These suggest that 5-ALA can sensitize certain cancer cells, but not normal cells, to thermal stress via accumulation of PpIX and increase of ROS generation.

Efficacy of concurrent chemoradiotherapy for T1 and T2 laryngeal squamous cell carcinoma regarding organ preservation.

BACKGROUND: Although the survival rate of early-stage laryngeal squamous cell carcinoma (SCC) patients treated by radiotherapy (RT) is sufficient, the larynx preservation rate is unsatisfactory. To improve the larynx preservation rate, such patients have been treated by RT with chemotherapeutic agents. PATIENTS AND METHODS: RT with or without uracil-tegafur (UFT) was performed for T1 cases, and UFT and carboplatin for T2 cases. RESULTS: In T1 cases, 30 patients received RT and 16 patients received concurrent chemoradiotherapy (CCRT). In T2 cases, 28 patients received RT and 45 patients received CCRT. There were no significant differences in the response and survival rates between the treatment methods both in T1 and T2 cases. The 5-year larynx preservation survival rate was improved significantly by CCRT in T2 cases (66.7% vs. 93.3%; p < 0.01). CONCLUSION: CCRT for early-stage laryngeal SCC patients was efficacious to improve the larynx preservation survival rate.

Early assessment of clinical response to concurrent chemoradiotherapy in head and neck carcinoma using fluoro-2-deoxy-d-glucose positron emission tomography.

OBJECTIVES: The aim of this study is to assess the utility of FDG-PET in the evaluation of therapeutic effects at 4 weeks after the completion of the concurrent chemoradiotherapy (CCR) in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Thirty-one patients with previously untreated HNSCC were retrospectively investigated about FDG-PET, CT, MRI and biopsies of the carcinoma before and 4 weeks after the treatment. RESULTS: The results of pathological examinations after CCR showed 6 residual cases and 25 ones with a pathologically complete response (pCR). The specificity of FDG-PET was 80%, although the sensitivity was limited to 67%. CONCLUSIONS: FDG-PET has a high specificity but limited sensitivity to discriminate residual cancer from fibrosis or scar at 4 weeks after CCR. FDG-PET at 4 weeks after CCR was too early to perform because of limited sensitivity.

Characterization of a novel human tumor antigen interleukin-13 receptor alpha2 chain.

The interleukin (IL)-13 receptor alpha2 (IL-13Ralpha2) chain is a primary binding and internalization subunit for a Th2-derived immune regulatory cytokine, IL-13. Although extremely high levels of IL-13Ralpha2 chain are expressed on a variety of human tumor cells and specimens, its precise role in tumor immunology has not been defined. To investigate the role of IL-13Ralpha2 in tumor immunity, we used D5 melanoma cells stably transfected with the human IL-13Ralpha2 gene (D5alpha2) to assess the effect of an IL-13Ralpha2 DNA vaccine in immunocompetent animals. Prophylactic immunization of mice with the IL-13Ralpha2 DNA vaccine resulted in protection against D5alpha2 tumor development. In vivo depletion experiments in C57BL/6 and RAG-2 knockout mice indicated that both T and B cells, but not natural killer cells, were required for the tumor protection. In addition, antibody induced by the IL-13Ralpha2 DNA vaccine showed a modest but significant inhibitory effect on D5alpha2 cells in vitro, suggesting that the antibody is biologically functional. The IL-13Ralpha2 DNA vaccine also exhibited antitumor activity against established D5alpha2 tumors in mice. Histologic analysis of regressing tumors identified infiltration of CD4+ and CD8+ T cells and the expression of CXCL9 chemokine in tumors. Taken together, our results identify the human IL-13Ralpha2 chain as a novel tumor rejection antigen.

Antitumor effects of ZD6474 on head and neck squamous cell carcinoma.

Angiogenesis is required for tumor growth and metastasis and, therefore, represents a target for cancer treatment. While many factors have been implicated in promoting angiogenesis, vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. ZD6474 is a potent VEGF receptor-2 (VEGFR-2) tyrosine kinase inhibitor which also has activity against the epidermal growth factor receptor (EGFR) tyrosine kinase. The purpose of this study was to investigate the sensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines to ZD6474, and to evaluate its antitumor efficacy on HNSCC xenografts. This is the first demonstration of antitumor effects of ZD6474 on HNSCC. In vitro ZD6474 displayed antiproliferative effects on HNSCC cells and inhibition of VEGFR-2 and EGFR pathways. In vivo ZD6474 displayed antitumor activity, induced apoptosis and antiangiogenic activity on nude mice bearing an established xenograft of YCU-H891 cells. These results suggest that ZD6474 has the potential to inhibit two key pathways in tumor growth via inhibition of VEGF-dependent tumor angiogenesis and via inhibition of EGFR-dependent tumor cell proliferation.

Anti-tumor effects of bevacizumab in combination with paclitaxel on head and neck squamous cell carcinoma.

Human tumors are dependent on angiogenesis for growth, and the vascular endothelial growth factor (VEGF) is a major regulator of this process. Bevacizumab (Avastin), a monoclonal antibody directed against VEGF, has shown promise in treating a variety of cancers. In this study, we first examined the anti-tumor effects of bevacizumab on head and neck squamous cell carcinoma (HNSCC). Then we examined the effects of bevacizumab combined with paclitaxel, a chemotherapeutic agent, in HNSCC. This is the first demonstration of the anti-tumor effects of bevacizumab on HNSCC. In vitro, bevacizumab did not show any antiproliferative effects against the HNSCC cell lines. However, in vivo, bevacizumab showed dramatic anti-tumor effects against HNSCC tumor xenografts in mice. In addition, treatment with a bevacizumab-paclitaxel combination resulted in a remarkable inhibition of the HNSCC tumor xenografts, compared to the effects of each agent separately. A decreased blood vessel density and an increased apoptotic index were seen in the shrunken tumors. These results suggest that bevacizumab in combination with paclitaxel could have useful clinical application in HNSCC.

Concurrent chemoradiotherapy for T4 patients with hypopharyngeal and laryngeal squamous cell carcinomas.

OBJECTIVES: Concurrent chemoradiotherapy (CCR) was given for the previously untreated T4 hypopharyngeal and laryngeal squamous cell carcinoma patients and the response and survival rates were evaluated. PATIENTS AND METHODS: A total of 23 patients, namely, 15 for hypopharynx and 8 for larynx were eligible. These patients were given cisplatin and 5-fluorouracil based chemotherapeutic regimens with conventional radiotherapy for a total dose of 66.6-70.2 Gy. RESULTS: Ten out of the 15 hypopharyngeal carcinoma patients and 4 out of the 8 laryngeal carcinoma patients showed a complete response at the primary sites. The 5-year disease-specific survival rate was 59.4% in all the patients, 51.9% in the hypopharyngeal carcinoma patients, and 71.0% in the laryngeal patients. Seven out of the 12 resectable hypopharyngeal carcinoma patients and 4 out of 8 laryngeal carcinoma patients were able to do without total laryngectomy. CONCLUSIONS: Based on these results, the survival rate in the hypopharyngeal and laryngeal T4 carcinoma patients treated by CCR seems to be satisfactory and the possibility of organ preservation for the advanced patients is indicated.

Expression and targeting of interleukin-4 receptor for primary and advanced ovarian cancer therapy.

Because the most characteristic property of ovarian cancer is i.p. spread, the majority of patients are diagnosed at an advanced stage, leading to limited availability of options for curative therapies. With an intent to identify targeted therapeutic approaches, we have observed that approximately 60% of 21 ovarian cancer tissue samples express a high density of interleukin-4 receptor (IL-4R), whereas normal ovarian tissues tested (n = 7) expressed no or low levels of IL-4R. To target IL-4R, we have developed IL-4 cytotoxin, in which circular-permuted IL-4 is fused to a mutated form of Pseudomonas exotoxin. This cytotoxin is specifically and highly cytotoxic to PA-1, IGROV-1, and SK-OV3 ovarian carcinoma cell lines in vitro. In addition, it shows remarkable antitumor activities against established s.c. ovarian tumors in immunodeficient animals. i.p. administration of IL-4 cytotoxin in mice with orthotopically implanted ovarian tumors caused regression of established tumors and prevented these animals from tumor metastasis. Continuous i.p. infusion of IL-4 cytotoxin prolonged survival of tumor-bearing mice even with bulky disease. These results indicate that IL-4R-targeted cytotoxin may be a useful agent for the management of patients with ovarian cancer, and further studies need to be done to evaluate its safety, tolerability, and efficacy.

Antitumor effects of IDN5109 on head and neck squamous cell carcinoma.

Taxanes, a new class of antitumor drugs, are effective against a large number of human tumors, although there are problems with drug resistance. The novel taxane, IDN5109, is characterized by its high tolerability, antitumor efficacy, ability to overcome multidrug resistance, and oral bioavailabilty. We investigated the cellular response of IDN5109 to head and neck squamous cell carcinoma (HNSCC), and compared the antitumor activity of IDN5109 with that of paclitaxel. This is the first demonstration of antitumor effects of IDN5109 on HNSCC. In in vitro experiments, IDN5109 showed antiproliferative effects against HNSCC cell lines. After treatment with IDN5109, Bcl-2 and Bcl-XL were down-regulated, Bax was up-regulated, and caspase-3 was activated. After treatment with IDN5109, concentrations of both VEGF and IL-8 in the culture supernatant of HNSCC cells decreased. In in vivo experiments, the oral administration of IDN5109 showed antitumor effects against HNSCC tumor xenografts. Immunohistochemistry showed that IDN5109 inhibited tumor angiogenesis and induced apoptosis in HNSCC cells, producing a decreased blood vessel density and increased apoptosis index. On the basis of these results, IDN5109 is useful as a chemotherapeutic agent against HNSCC.

Fibromatous polyp of the hypopharynx.

We treated a patient with hypopharyngeal fibromatous polyp and speculated the mechanism of this disease. Fibromatous polyp, consisting of fibrous tissue hyperplasia with small vessels, fatty cells and inflammatory cells, is a clinically diagnostic name. Most of pharyngeal fibromatous polyps are arising from the palatine tonsil, and those from the pharyngeal epithelium are rare. The greater part of hypopharyngeal tumors is squamous cell carcinomas, and benign tumors are really uncommon. Fibromatous polyp is not thought to be a true tumor, but the symptoms are almost the same as tumorous diseases, e.g., discomfort in the throat, swallowing difficulty and respiratory distress. Complete resection is used as the treatment method. We operated on this patient under a laryngoscope and successfully resected the polyp. Five months after the operation, there is no sign of recurrence and the patient has no symptoms. This type of polyp is considered to enlarge gradually and it can cause asphyxia and/or dysphagia, so complete ablation should be performed as soon as possible.

Targeting interleukin-4 receptors for effective pancreatic cancer therapy.

We demonstrate that pancreatic cancer tissues express receptors for interleukin (IL)-4 in situ at high density. Using the approach of selective receptor targeting, we have tested the efficacy of a recombinant cytotoxin IL4-Pseudomonas exotoxin A, which is composed of a targeting moiety (IL-4) and a mutated form of Pseudomonas exotoxin. Our results demonstrate that this molecule exerts vigorous antitumor activity against human pancreatic tumors implanted s.c. in immunodeficient animals. Sixty percent of animals treated with intratumoral injections of IL4-Pseudomonas exotoxin A experienced complete disappearance of established tumors. Animals with pancreatic tumors implanted orthotopically exhibited prolonged survival that was significantly greater by comparison with untreated animals. Thus, IL-4 receptor-targeted cytotoxin represents a potent agent that may provide an effective therapy for pancreatic cancer.

[Change of creatinine clearance rate in accordance with aging in Japanese patients with head and neck cancer].

Most of the head and neck tumors are squamous cell carcinomas (SCCs), which are relatively sensitive to chemotherapeutic agents. Cis-platinum (CDDP), 5-fluorouracil and taxanes are widely used worldwide for SCCs, and CDDP is the most common agent. Renal toxicity is a well-known adverse effect of CDDP, and adequate pre and post-hydration or combined administration of neutralizing agents is performed during CDDP injection. Before the CDDP administration, we have to evaluate renal function of the patients using creatinine clearance rate (Ccr). In Japan, CDDP at the dose of 60-70 mg/m(2)/day is administered in cases with over 65 ml/min/1.73 m(2) of Ccr, whereas in cases under 60 ml/min/1.73 m(2), we use other drugs, e.g., carboplatin, to prevent the renal dysfunction followed by chemotherapy. In other countries, the dose of CDDP is 70-100 mg/m(2)/day, and the discrepancy is based on the poor renal function of Japanese. We calculated Ccrs of 107 head and neck cancer patients since January, 2004 to August, 2005, and evaluated renal function before any treatment. Ccr was decreased in proportion to aging. At the age of fifties, 43.5% of the patients indicated lower Ccr than 65 ml/min/1.73 m(2): sixties, 45.7%; seventies, 50.0%; and eighties, 85.7%. In the United States, the average glomerular filtration rate of over 70 year-old healthy people is estimated as 75 ml/min/ 1.73 m(2), and it is considered sufficient kidney function for the administration of CDDP at the dose of 70-100 mg/ m(2)/day. The incident rate of end-stage renal disease is 1.3 times higher in the United States than in Japan. The incident rate of diabetes, which is the main cause of renal dysfunction, is almost the same in both countries. Though the reason is unclear, it is the fact that the renal function of Japanese decreases quickly in accordance with aging.

[Corrigendum] Antitumor effects of IDN5109 on head and neck squamous cell carcinoma.

Oncol Rep 15: [Related article:] 329­334, 2006; DOI: 10.3892/or.15.2.329 After the publication of the article, the authors noted that the relevance of the findings reported in this article on IDN5109 inhibition of growth of head and neck squamous cell carcinoma (HNSCC) is now in question. To examine the antitumor effect of IDN5109, this study was conducted using YCU-H891 and KCC-MS871 cell lines that the authors believed to be HNSCC cell lines. Because different human leukocyte antigen (HLA) was detected in 2 cell lines (KCC-TCM901 and KCC-T873) which were derived from the same patient in an experiment after publication, 16 cell lines established in our institution were analyzed by short tandem repeat (STR) analysis. STR analysis revealed that genotype of KCC-TCM901, YCU-H891 and KCC-MS871 was identical to that of HeLa cells, and that genotype of YCU-T891 was identical to that of YCU-L891, which was considered to be cross-contamination.

[Corrigendum] Antitumor effects of ZD6474 on head and neck squamous cell carcinoma.

Oncol Rep 17: [Related article:] 289­295, 2007; DOI: 10.3892/or.17.2.289 After the publication of the article, the authors noted that the relevance of the findings reported in this article on ZD6474 inhibition of growth of head and neck squamous cell carcinoma (HNSCC) is now in question. To examine the antitumor effect of ZD6474 in vitro and in vivo, this study was conducted using YCU-H891 cell line that the authors believed to be HNSCC cell line. Because different human leukocyte antigen (HLA) was detected in 2 cell lines (KCC-TCM901 and KCC-T873) which were derived from the same patient in an experiment after publication, 16 cell lines established in our institution were analyzed by short tandem repeat (STR) analysis. STR analysis revealed that genotype of KCC-TCM901, YCU-H891 and KCC-MS871 was identical to that of HeLa cells, and that genotype of YCU-T891 was identical to that of YCU-L891, which was considered to be cross-contamination.

Molecular design and biological activities of protein-tyrosine phosphatase inhibitors.

Protein-tyrosine kinase (PTKase) and protein-tyrosine phosphatase (PTPase) regulate the intracellular signal transduction in various biological processes. PTPase often negatively regulates the intracellular protein-tyrosine phosphorylation. PTPases are considered to be involved in the etiology of diabetes mellitus and neural diseases, such as Alzheimer's disease and Parkinson's disease. Therefore, PTPase inhibitors should be useful tools to study the role of PTPases in these diseases and other biological phenomena, and they hopefully may be developed into chemotherapeutic agents. We first discovered a naturally occurring PTPase inhibitor, dephostatin, in 1993. Later, we developed stable and safe dephostatin analogues by a molecular design approach employing the concept of CH/pi interaction. We prepared Et-3,4-dephostatin as a stable analogue and found it to inhibit PTP-1B and SHPTP-1 PTPases selectively. Et-3,4-dephostatin increased the tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), with or without insulin, in differentiated 3T3-L1 mouse adipocytes. It also increased the phosphorylation and activation of Akt. The analogue also enhanced translocation of glucose transporter 4 (GLUT4) from the cytoplasm to the membrane and 2-deoxyglucose transport. It also showed an in vivo antidiabetic effect in terms of reducing the high blood glucose level in KK-Ay mice after oral administration. Since Et-3,4-dephostatin contains a nitrosamine moiety, we designed nitrosamine-free dephostatin analogues employing the concept of CH/pi interaction. Then, we synthesized methoxime- and hexyl-methoxime-3,4-dephostatin as nitrosamine-free analogues. These analogues also showed antidiabetic activity in vivo and illustrate the utility of the CH/pi interaction molecular design approach.

Combined effects of radiation and interleukin-13 receptor-targeted cytotoxin on glioblastoma cell lines.

PURPOSE: Interleukin-13 receptor-targeted cytotoxin (IL13-PE38) is highly cytotoxic to human glioblastoma (GBM) cells. Although this molecule is being tested in a multicenter Phase III clinical trial (PRECISE Study) in patients with recurrent disease, the activity of IL13-PE38 when combined with radiation therapy has not been investigated. METHODS AND MATERIALS: Cytotoxicity of IL13-PE38 to GBM cell lines was assessed by protein synthesis inhibition and clonogenic assays, and the growth of GBM cells receiving radiation was assessed by thymidine uptake assays. Expression of IL-13 receptor alpha2 (IL-13Ralpha2) messenger ribonucleic acid (mRNA) in GBM cells exposed to radiation was assessed by quantitative reverse transcriptase/polymerase chain reaction (RT-PCR) and IL-13R density by radiolabeled IL-13 binding assays. RESULTS: Prior irradiation of GBM cell lines followed by IL13-PE38 treatment did not enhance cytotoxicity; however, concomitant 5 Gy irradiation and IL13-PE38 treatment was highly cytotoxic to T98G, M059K, A172, and LN-229 cell lines as determined by cell viability assays. There was a statistically significant decrease in number of viable cells in IL13-PE38 and irradiated cells compared with irradiated cells alone (p < 0.05) or IL13-PE38 treated cells alone (p < 0.05). In contrast, U251, SN19, and U87MG cell lines did not show any combined effect. These results were confirmed by clonogenic assays. Although three GBM cell lines-U251, SN19, and A172-showed 2.8- to 13.9-fold upregulation of IL-13Ralpha2 mRNA expression at 6-24 h after exposure to 5 Gy radiation, specific binding of radiolabeled IL-13 to these cell lines did not improve. CONCLUSIONS: Our results suggest that concomitant radiation therapy and IL13-PE38 treatment may be beneficial for the treatment of patients with GBM. This strategy may be worth exploring in animal models of human glioma.

Nitric oxide accelerates interleukin-13 cytotoxin-mediated regression in head and neck cancer animal model.

Receptors for interleukin-13 (IL-13R) are overexpressed on several types of solid cancers including gliobastoma, renal cell carcinoma, AIDS Kaposi's sarcoma, and head and neck cancer. Recombinant fusion proteins IL-13 cytotoxin (IL13-PE38QQR or IL13-PE38) have been developed to directly target IL-13R-expressing cancer cells. Although it has been found that IL-13 cytotoxin has a direct potent antitumor activity in vivo in nude mice models of human cancers, the involvement of indirect antitumor effecter molecules such as nitric oxide (NO) is unknown. To address this issue, we assessed the effect of NO inhibiter N(omega)-monomethyl-l-arginine on IL-13 cytotoxin-mediated cytotoxicity and NO2/NO3 production in HN12 head and neck cancer cells. In addition, antitumor effects and NO levels in HN12 and KCCT873 head and neck tumors xenografted s.c. in nude mice when treated with IL-13 cytotoxin were evaluated by tumor measurement, Western blot, and immunohistochemistry analyses. Pretreatment of animals with N(omega)-monomethyl-l-arginine significantly decreased the NO levels and IL-13 cytotoxin-mediated antitumor effects. In addition, depletion of macrophages, known to produce NO, also decreased antitumor activity of IL-13 cytotoxin. Based on these studies, we concluded that NO accelerates antitumor effect of IL-13 cytotoxin on head and neck tumor cells. Because IL-13 cytotoxin is currently being tested in the clinic for the treatment of patients with recurrent glioblastoma maltiforme, our current findings suggest maintaining macrophage and NO-producing cellular function for optimal therapeutic effect of this targeted agent.

Effect of interleukin (IL)-4 cytotoxin on breast tumor growth after in vivo gene transfer of IL-4 receptor alpha chain.

Although human breast cancer cells express interleukin-4 receptors (IL-4Rs), a recombinant fusion protein, IL-4 cytotoxin, did not mediate desirable antitumor activity in tumor models of breast cancer. Recent studies have identified that a primary IL-4 binding protein, IL-4Ralpha chain, is internalized after binding to IL-4 in cancer cells. The consequent expression of high-level IL-4Ralpha in tumor cells sensitizes them to the cytotoxic effect of IL-4 cytotoxin in vitro. To assess whether overexpression of IL-4Ralpha chain in vivo by plasmid-mediated gene transfer can enhance antitumor activity of IL-4 cytotoxin in mouse models of breast tumor, we injected MDA-MB-231 human breast cancer cells in both flanks of athymic nude mice. Animals then received three intratumoral (i.t.) injections of either IL-4Ralpha encoding vector (left flank) or vector only (right flank) mixed with liposome followed by IL-4 cytotoxin administration. Both i.p. and i.t. administration of IL-4 cytotoxin profoundly reduced the growth of IL-4Ralpha plasmid-injected MDA-MB-231 tumors, compared with control. Innate immune cells, including macrophages and neutrophils, were found to infiltrate at the regressing tumor site. This study provides proof of principle that i.t. IL-4Ralpha plasmid injection followed by systemic or i.t. IL-4 cytotoxin administration may be a useful strategy for the treatment of breast cancer.

Internalization property of interleukin-4 receptor alpha chain increases cytotoxic effect of interleukin-4 receptor-targeted cytotoxin in cancer cells.

Although the receptor for interleukin-4 (IL-4R) is highly expressed on solid human cancer cells, its significance and internalization function is still unclear. To address these issues, we reconstituted Chinese hamster ovarian (CHO-K1) cells with various components of the IL-4R by transient transfection and performed internalization assays using radiolabeled IL-4. Radiolabeled IL-4 internalized through the IL-4Ralpha chain in a time-dependent manner. When the IL-4Ralpha chain was cotransfected with the IL-13Ralpha1 or -gamma(c) chain, the IL-4 internalization level was identical to IL-4Ralpha transfectants, suggesting that the IL-4Ralpha chain plays a major role in IL-4 internalization. These results were confirmed by determining the cytotoxicity of a chimeric protein composed of IL-4 and a mutated form of Pseudomonas exotoxin [IL4(38-37)-PE38KDEL] in CHO-K1 cells transfected with increasing concentrations of IL-4Ralpha cDNA. To use the internalization property of the IL-4Ralpha chain in the context of IL-4R-targeted cytotoxin therapy, we transiently transfected pancreatic and brain tumor cells with IL-4Ralpha chain. Surprisingly, these tumor cells acquired 4-75-fold higher binding activity to IL-4 compared with control cells. Consequently, the cytotoxic activity of IL-4 toxin to these cancer cells was enhanced 5-13-fold compared with control cells as assessed by protein synthesis inhibition and clonogenic assays. Taken together, a combination approach that involves transfer of the IL-4Ralpha gene and IL-4R-targeted cytotoxin therapy may serve as a novel approach for cancer therapy.

Interleukin-13 receptor alpha2 chain in human head and neck cancer serves as a unique diagnostic marker.

Previous studies have demonstrated that approximately 30% of squamous cell carcinoma of the head and neck (SCCHN) cell lines express high levels of interleukin-13 receptor(s) (IL-13R). However, the incidence, expression level, and significance of IL-13R expression in human tumor specimens is not known. In addition, it is not known whether normal head and neck tissues express IL-13R. In this study, we evaluated the expression of IL-13R subunits (IL-13Ralpha1, IL-13Ralpha2, and IL-4Ralpha) in 337 surgically excised specimens of SCCHN and normal head and neck tissues. Specimens were obtained from 139 patients with SCCHN and 16 patients with benign tonsil disorders from two centers in the United States and Japan and evaluated with immunohistochemistry and in situ hybridization. Extensive analysis demonstrated that the majority of SCCHN tumors uniformly expressed low levels of IL-13Ralpha1 chain; however, 77% of the tumors expressed moderate to high levels of IL-4Ralpha, which forms a signaling complex with IL-13Ralpha1 chain. On the other hand, 33% of SCCHN tumors expressed moderate to high levels of IL-13Ralpha2 chain. Using tissue array from 99 patients, we observed that the expression levels of IL-13Ralpha2 and IL-4Ralpha were significantly higher in SCCHN than in normal head and neck tissues (P < 0.005). Detailed analysis of clinicopathological features demonstrated a positive statistically significant correlation between IL-13Ralpha2 expression and clinically advanced primary SCCHN tumor (T(4); Tumor-Node-Metastasis classification; P < 0.05). However, there was no correlation among IL-13R expression and sex, age of patients, stage of lymph node metastasis, squamous cell carcinoma grade, or allergic history. Taken together, this study suggests that IL-13R may be involved in SCCHN tumor progression, and 33% of IL-13Ralpha2-positive SCCHN cases may be targeted by IL-13 cytotoxin and IL-13R-targeted agent.