Interleukin-13 receptor-targeted cancer therapy in an immunodeficient animal model of human head and neck cancer

Although interleukin-13 receptors (IL-13R) are overexpressed on several head and neck cancer cell lines, a majority of cell lines express only low levels of IL-13R. We have found that the primary interleukin-13-binding protein IL-13Ralpha2 chain plays an important role in ligand binding and internalization. We showed that the gene transfer of IL-13Ralpha2 chain into various solid tumor cell lines that express few IL-13Rs can dramatically sensitize cells to the cytotoxic effect of a recombinant chimeric protein composed of interleukin-13 and a mutated form of Pseudomonas exotoxin A, IL13-PE38QQR. Based on the expression of IL-13R, we have classified five head and neck cancer cell lines into two groups: (a) IL-13Ralpha2 chain-positive cell lines (SCC-25 and KCCT873); and (b) IL-13Ralpha2 chain-negative cell lines (A253, YCUT891, and KCCT871). By plasmid-mediated stable gene transfer, we demonstrate that not only IL-13Ralpha2 chain-positive head and neck cancer cell lines but also IL-13Ralpha2 chain-negative cell lines can dramatically increase sensitivity to IL-13 toxin by 520-1000-fold compared with mock-transfected control cells after genetic alteration to express high levels of the IL-13Ralpha2 chain. In animal studies, i.p. or intratumoral administration of IL13-PE38QQR given daily or on alternate days for 3-5 days showed dramatic tumor response with complete remission in intratumorally injected tumors in both IL-13Ralpha2 chain-positive and -negative but transfected with IL-13Ralpha2 chain head and neck tumor implanted s.c. in nude mice. These results demonstrate that by using a combination approach of gene transfer and systemic or locoregional cytotoxin therapy, the IL-13R represents a new potent target for head and neck cancer therapy.     

Chemotherapy in head and neck cancer.

The role of chemotherapy in the management of patients with head and neck cancer continues to evolve. Single-agent methotrexate or cisplatin, or the combination of cisplatin and infusional fluorouracil can be considered standard therapy for patients with recurrent disease. Neoadjuvant chemotherapy is being actively pursued. Although enhanced survival has not yet been demonstrated, the goal of organ preservation has been achieved for patients with laryngeal cancer. Because of the high incidence of locoregional failure, concomitant chemoradiotherapy is also under investigation. This treatment approach has already been suggested to result in prolonged survival in randomized studies and holds promise for the future.     

Predictive factors in head and neck cancer.

As new knowledge of the molecular mechanisms of tumor development and progression is gained, studies are required to determine whether specific molecular genetic changes might be useful indicators in selecting patients for specific therapies. Alternatively, molecular or genetic changes may identify the patients at greatest risk for progression and relapse so that they can be treated with adjuvant therapy. p53 has an important function in the regulation of the cell cycle, DNA repair, and programmed cell death pathways. The Bcl-2 protein family has gained recent attention for its role in permitting or blocking apoptosis. Interaction between p53, Bcl-2, and other products of tumor suppressor genes or oncogenes are probably critical in tumor progression and response to treatment.     

CEA levels in head and neck cancer.

Serum carcinoembryonic antigen (CEA) levels were determined for 439 patients with squamous carcinoma of the head and neck region, 154 healthy smokers, and 122 nonsmokers. Among nonsmokers 95% of the CEA levels did not exceed 5 ng/ml, but among smokers this discriminatory level was 7 ng/ml. Among tumor-bearing patients 36% of the CEA levels exceeded 5 ng/ml but only 17% exceeded 7 ng/ml. Both the incidence and magnitude of CEA elevations correlated with clinical stage of tumor; however, excluding patients with clinically apparent advanced malignancies, the incidence and magnitude of elevations were similar among tumor-bearing patients, tumor-free treated patients, and smokers. Although not predictive of ultimate survival, elevated preoperative CEA levels declined to the range of normals after resection. Similarly, during palliative irradiation for incurable tumors, CEA levels declined with regression of tumor. Irradiation did not nonspecifically elevate CEA levels. The data indicate that in patients with head and neck squamous carcinomas CEA level is not likely to contribute to a determination of prognosis after therapy; however, serial determinations may have adjunctive value in monitoring tumor response.     

Interleukin-1 beta and interleukin-6 release by peripheral blood monocytes in head and neck cancer.

In patients with advanced head and neck squamous cell carcinoma (HNSC), evidence of cell-mediated immunity and monocyte functional abnormalities has been reported. We studied the production of interleukin 1 beta (IL-1 beta) and interleukin 6 (IL-6) by peripheral blood monocytes from 22 patients with HNSC (12 larynx and ten oral cavity cancers) in comparison with monocyte cytokine production of age-matched healthy subjects. Pure monocytes were incubated with and without lipopolysaccharides (LPS) (10 micrograms ml-1) for 4 h at 37 degrees C and IL-1 beta and IL-6 concentrations were determined in supernatants by specific ELISA. There was no significant difference in IL-1 beta levels in monocyte supernatants from cancer in comparison to control subjects; conversely, a higher IL-6 production by unstimulated and LPS-activated cells from HNSC patients than from controls was found. No relationship was observed between cytokine production and cancer stage. The regression analysis evidenced a significant correlation between IL-1 beta and IL-6 monocyte-release in HNSC patients and in controls, so suggesting a possible autocrine control of IL-6 production by other cytokines.     

Staging of head and neck cancer.

Revised staging systems for cancers of the upper aerodigestive tract, the major salivary glands, and the thyroid are presented. The staging has been accepted by both the American Joint Committee on Cancer and the International Union Against Cancer and is gaining worldwide acceptance.     

Induction of tumor regression in experimental model of human head and neck cancer by human A-LAK cells and IL-2

In a nude mouse model of human squamous-cell carcinoma of the head and neck (SCCHN), locoregional therapy with interleukin 2 and human lymphokine-activated killer (LAK) cells resulted in a significant inhibition of growth of 3-day established tumors. The same model was used for therapy of 7-day established tumors with highly enriched populations of human adherent (A)-LAK (CD3- CD56+) cells and IL-2. Peritumoral transfer of 10 x 10(6) A-LAK cells, whose in vitro cytotoxicity against a SCCHN cell line (PCI-I) was not significantly different from that of LAK cells, resulted in complete regression of all 3-day or 7-day human SCCHN in nude mice. An initial inflammatory-type reaction, which appeared within hours of the first peritumoral cell transfer, was accompanied by infiltration initially by granulocytes and plasma cells, and later by mononuclear cells into the tumor stroma. A-LAK cells labelled with a fluorescent dye prior to injection appeared in the tumor stroma within 24 hr and were localized around or in the basal epithelial tumor layer by 48 hr. Histologic sections revealed an increasing epithelial disorganization and progressively decreasing basal epithelial layer, which were proportional to the increasing number of A-LAK cells transferred. Within 4 weeks, the tumors were reduced to amorphous keratinic remnants surrounded by the connective tissue containing abundant mononuclear cells. Local administration of human A-LAK cells and IL-2 to SCCHN tumors growing in nude mice led to accelerated tumor differentiation, keratinization and regression.     

Endoscopic near-infrared photoimmunotherapy in an orthotopic head and neck cancer model

Near-infrared photoimmunotherapy (NIR-PIT) is a cell selective cancer therapy that uses an antibody-photoabsorber (IRDye700DX, IR700) conjugate (APC) and NIR light. NIR-PIT targeting epidermal growth factor receptor (EGFR) in head and neck cancer (HNC) was conditionally approved in Japan in 2020. APC-bound tumors can be detected using endoscopic fluorescence imaging, whereas NIR light can be delivered using endoscopic fiber optics. The aims of this study were: (1) to assess the feasibility of endoscopic NIR-PIT in an orthotopic HNC model using a CD44-expressing MOC2-luc cell line; and (2) to evaluate quantitative fluorescence endoscopic imaging prior to and during NIR-PIT. The results were compared in 3 experimental groups: (1) untreated controls, (2) APC injection without light exposure (APC-IV), and (3) APC injection followed by NIR light exposure (NIR-PIT). APC injected groups showed significantly higher fluorescence signals for IR700 compared with the control group prior to therapeutic NIR light exposure, and the fluorescence signal significantly decreased in the NIR-PIT group after light exposure. After treatment, the NIR-PIT group showed significantly attenuated bioluminescence compared with the control and the APC-IV groups. Histology demonstrated diffuse necrotic death of the cancer cells in the NIR-PIT group alone. In conclusion, endoscopically delivered light combined with quantitative fluorescence imaging can be used to “see and treat” HNC. This method could also be applied to other types of cancer approachable with endoscopy.     

一氧化氮与肿瘤转移

一氧化氮(NO)的生物学活性广泛,多种肿瘤组织存在一氧化氮合成酶(NOS)表达异常和(或)NO产生异常.宿主和肿瘤细胞的NOS表达及NO合成差异,对肿瘤细胞的生存和转移潜能有不同影响.研究NO及NOS在肿瘤细胞转移过程中的效应机制,有望发现防治肿瘤转移的潜在靶点.     

Immunologic effector cells in head and neck cancer.

Freshly isolated tumor-infiltrating lymphocytes (TIL) and lymph node lymphocytes (LNL) in patients with head and neck cancer (HNC) often have low or undetectable functional responses. Because impaired ability of these cells to produce cytokines could be responsible for their functional incompetence, spontaneous and in vitro-induced production of interleukin-2 (IL2), interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and interferon gamma (IFN-gamma) by TIL, LNL from tumor-free as well as tumor-involved lymph nodes (LN), and peripheral blood lymphocytes (PBL) were measured. Although TIL or PBL of patients with HNC produced IL-1 beta and TNF-alpha spontaneously or after in vitro activation, LNL did not produce measurable levels of these cytokines. LNL also produced lower levels of IFN-gamma than PBL. In situ hybridization for cytokine mRNA performed with tumor tissues, and LN of patients with HNC showed that TIL as well as LNL localized in the immediate proximity of the tumor were activated, as evidenced by the expression of mRNA for IL2, IFN-gamma, IL-1 beta, TNF-alpha, and both alpha- and beta-chains of the IL2 receptor. In addition, many LNL located next to the tumor expressed mRNA for transforming growth factor-beta (TGF-beta). In contrast, LNL not adjacent to the tumor in involved LN, as well as those in tumor-uninvolved LN, did not express mRNA for cytokines or IL2 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chemoprevention in head and neck cancer

It is not a coincidence that the aerodigestive tract has proven such a fertile ground for the evaluation of chemoprevention. The incidence of second primaries and the concept of field cancerization made the need for prevention acute and showed the limitations of even the most curative of treatments. New and presumably less toxic agents are being evaluated; chemoprevention is being applied to asymptomatic populations at higher risk for lung, colon, breast, and other neoplasias. Biomarkers may be instrumental in rapid development of these new clinical applications, but much is still to be done. Yet unanswered is whether suppression of premalignant lesions will ultimately decrease cancer incidence. Survival in the second primary prevention trial has not thus far shown a significant improvement and toxicities were significant. Many questions remain in the study of chemoprevention; head and neck cancer provides a conducive model in which these answers might be found.     

Radiochemotherapy in head and neck cancer

The present paper is based on a talk given, during the meeting of the EORTC Radiotherapy Group, held in Arona (Italy) on April 19-20, 2002. This review analyses many still open questions on combined chemotherapy and radiotherapy in head and neck cancer, on the basis of the available data.The paper may help to point out future directions for novel clinical researches on combined chemotherapy and radiotherapy in head and neck cancer.     

Cytogenetics in head and neck cancer

Cytogenetics or the study of chromosomes has been an important tool in oncology. It localizes the abnormality on a particular chromosome segment as such but, the molecular analysis on the other hand focuses the exact gene of interest. Hence both are complimentary. Classical cytogenetics in combination with recent molecular techniques has given rise to various molecular cytogenetic analytical techniques such as florescent in-situ hybridization (FISH), spectral karyotyping (SKY) and comparative genomic hybridization (CGH). The role of telomeres and its concerned enzyme telomerase is important in carcinogenesis. This article summarizes the various cytogenetic techniques and presents an overall view of the importance of cytogenetcs in head and neck cancer.     

Combination chemotherapy of head and neck cancer.

A total of 77 patients with cancer of the head and neck area were treated with five different drug combination regimens. Five of the 77 patients had lymphoepithelioma; four had adenocystic carcinoma, and 68 had squamous-cell carcinoma of the head and neck (16 from the skin). Of these 77 patients, 16 had no previous treatment, five had surgery, 11 had radiotherapy, and 45 had surgery and radiotherapy. The first regimen consisted of a four-day Bleomycin infusion followed after a 24-hour rest, by cyclophosphamide (Cytoxan), Vincristine (Oncovin), methotrexate and 5-Fluorouracil (5-FU) (B-COMF). The next three regimens consisted of a four-day Bleomycin course, followed by either Cytoxan and methotrexate (B-CM), Cytoxan and 5-FU (B-CF) or Methotrexate and 5-FU (B-MF). The fifth regimen consisted of Bleomycin concomitant with Cytoxan, Methotrexate, and 5-FU (B-CMF). Of the 49 patients receiving B-COMF and B-CMF, 12 showed a complete response and 12 a partial response. Among the 28 patients receiving Bleomycin, followed by any one of the two drug regimens, only six showed a partial response. The severity of the thrombocytopenia, number of drugs, lymphoepithelioma histology and performance status of the patient influenced the rate of response. Drug toxicity consisted mostly in myelosuppression. The B-CMF combination is highly effective and can be used as an adjuvant to surgery and/or radiotherapy.