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Glutathione S-transferase omega 2 (GSTO2) lacks any appreciable GST activity, but it exhibits thioltransferase activity. The significance of GSTO2 in lung function has been reported; however, the precise expression and molecular function of GSTO2 in the lungs remain unclear. In the present study, we found that GSTO2 is expressed in airway basal cells, non-ciliated, columnar Clara cells, and type II alveolar cells, which have self-renewal capacity in the lungs. Contrastingly, no GSTO2 expression was observed in 94 lung squamous cell carcinoma (LSCC) samples. When human LSCC cell lines were treated with 5-aza-2'-deoxycytidine, a DNA-methyltransferase inhibitor, GSTO2 transcription was induced, suggesting that aberrant GSTO2 hypermethylation in LSCC is the cause of its downregulation. Forced GSTO2 expression in LSCC cell lines inhibited cell growth and colony formation in vitro. In a subcutaneous xenograft model, GSTO2-transfected cells formed smaller tumors in nude mice than mock-transfected cells. Upon intravenous injection into nude mice, the incidence of liver metastasis was lower in mice injected with GSTO2-transfected cells than in those injected with mock-transfected cells. In addition, GSTO2 induction suppressed the expression of β-catenin and the oxygen consumption rate, but it did not affect the extracellular acidification rate. Furthermore, GSTO2-transfected cells displayed lower mitochondrial membrane potential than mock-transfected cells. When GSTO2-transfected cells were treated with a p38 inhibitor, β-catenin expression and mitochondrial membrane potential were recovered. Our study indicated that the loss of GSTO2 via DNA hypermethylation contributes to the growth and progression of LSCC, probably by modulating cancer metabolism via the p38/β-catenin signaling pathway., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

A patient was 70-year-old female. Because unknown fever following operation of left knee in December 20XX-1, abdominal simple CT was performed, diagnosed as cholecystitis and liver abscesses. However, her unknown fever did not improve with antibiotics therapy. Abdominal enhanced CT and MRI revealed to gallbladder cancer with liver invasion and metastases. These lesions were relatively localized in liver S4a/S5 and gallbladder, hepatoduodenal mesentery. Because unknown fever was exhausting, cholecystectomy, S4a+S5 hepatectomy with extrahepatic bile duct resection and lymph node dissemination were performed in January 20XX+1. In these pathological findings, there were moderate to poorly differentiated adenocarcinoma with squamous cell differentiation in almost area of gallbladder, diagnosed as adeno-squamous carcinoma with liver invasion and metastasis(pT3a[SI][H-inf], int, INF-β, ly1, v3, pn1, pN1, pM1, pStage ⅣB). One months after operation, abdominal CT revealed multiple liver metastatic recurrences. She died 7 months after operation. Although gallbladder adeno-squamous carcinoma has a poor prognosis, these many cases had a tendency to local infiltration accompanied with tumor fever. If curative resection might be obtained and the symptoms might be improved, aggressive resection should be performed.

Background: The aim of this study was to evaluate the association between the expression of programmed death ligand-1 (PD-L1) and clinical outcomes in patients with surgically resected esophageal squamous cell carcinoma (ESCC)., Materials and Methods: We included 76 patients with primary ESCC who underwent surgical resection between January 2009 and December 2014 at National Defense Medical College Hospital. Using the tumor tissues, we evaluated PD-L1 expression in tumor cells and stromal reactive lymphocytes via immunohistochemistry. Furthermore, the relationship between PD-L1 expression and the clinicopathological status of patients with ESCC was investigated., Results: PD-L1 expression in tumor cells was detected in 39.5% of the patients. In addition, 51.3% of the patients had PD-L1-positive stromal reactive lymphocytes and exhibited significantly longer overall survival than those with lack of PD-L1 expression in stromal reactive lymphocytes (median survival time, 56.0 versus 27.3 mo; log-rank test, P = 0.04). Patients with lack of PD-L1 expression in both tumor cells and stromal reactive lymphocytes showed worse overall survival than those with the PD-L1-positive expression in tumor cells and/or stromal reactive lymphocytes (P = 0.02)., Conclusions: PD-L1-positive expression in stromal reactive lymphocytes, rather than in tumor cells, is associated with a longer survival in patients with ESCC., (Copyright © 2020. Published by Elsevier Inc.)

The recommended S-1 chemotherapy schedule for head and neck cancer is daily treatment for 4 weeks, followed by 2 weeks of rest. However, this can lead to adverse events and sometimes treatment withdrawal. Alternate-day treatment with a pyrimidine anticancer agent is reported to reduce adverse events without compromising anticancer activity. We examined the indication of alternate-day treatment with S-1 for oral cancer. Fifteen patients(3 men and 12 women; average age: 81.3 years)with oral squamous cell carcinoma started consecutive-day treatment with S-1. Treatment had to be interrupted after 0.5-10 courses because of grade >2 myelosuppression, hepatorenal and electrolyte disorder, and grade 1 digestive toxicity. After a recovery period of 8-168 days from adverse events, alternate-day treatment with S-1 was started. Adverse events on this regimen were grade 2 leucopenia and hyperbilirubinemia in some patients. It was possible for 10 of the patients to continue this treatment for longer than 1 year or until death, but 5 patients could not continue because of a recurrence of a renal or electrolyte disorder, pneumonia, or disease progression. It is thought that alternate-day treatment with S-1 reduces the incidence of adverse events compared to consecutive-day treatment, and can allow continuous administration. Alternateday treatment with S-1 for female patients aged over 80 years with grade 1 leucopenia and/or thrombocytopenia before administration may help to maintain their quality of life.

The use of a rectangular flap is a well known technique for upper lip repair in cleft lip, but is less common for lower lip repair after tumour resection. We have found this type of flap to be favourable for lower lip reconstruction, especially for the lip to mental region. We describe herein an improvement to the technique in which two opposing rectangular flaps, with the length of one side equal to the vertical distance from the mentolabial groove to the vermilion border, were raised on the lateral sides of a U-shaped defect. Reconstruction was performed by interdigitation of the two flaps and a bilateral vermilion advancement flap. This new approach allows a distinct mentolabial groove and mental protuberance to be created by utilizing two opposing rectangular flaps and redundant tissue, without sacrificing sensation and muscle function. Our results suggest that the technique provides excellent functional and cosmetic outcomes in restoration of the lower lip in properly selected patients., (Copyright © 2014 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

A large full-thickness defect of the lower lip is difficult to reconstruct. Preservation of eating and speaking functions based on maintenance of oral sphincter and muscle function, sensation, and the oral aperture are the basic aims. It is also important to achieve a good aesthetic appearance. Here, we describe a new procedure using combined bilateral hatchet and nasolabial advancement flaps for a large full-thickness defect of the lower lip. The aim of use of the hatchet flap is to make a natural curve from the mentolabial fold to the mental protuberance using the "dog ear" resulting from suturing medially advanced bilateral hatchet flaps and to preserve a more certain blood supply to the medial edge of the flap. Our results indicate that the procedure using combined bilateral hatchet flaps and nasolabial flaps is useful for a U-shaped large full-thickness defect, with good functional and aesthetic outcomes.

microRNAs (miRNAs) are involved in cancer pathogenesis, apoptosis and cell growth, thereby functioning as both tumor suppressors and oncogenes. However, the expression patterns and roles of miRNAs in oral squamous cell carcinoma (OSCC) remain largely unknown. We hypothesized that oral cancer may have a unique miRNA profile, which in turn may play a critical role in oral cancer development, progression, diagnosis and prognosis. We, therefore, investigated the expression profiles of 29 OSCC tumors and 7 normal oral mucosal samples. The miRNA expression patterns in OSCC were examined by TaqMan-based microRNA assays. We were subsequently able to identify the candidates of cancer-related miRNAs through analysis of the miRNA expression profiles. In conclusion, OSCC tissues were shown to have a unique miRNA profile pattern when compared with that in normal tissues. The present study may provide useful information for further investigation of the functional roles of miRNAs in OSCC development, progression, diagnosis and prognosis.

Objective: L-3-[(18)F]-fluoro-α-methyl tyrosine ((18)F-FAMT) is an amino acid tracer for positron emission tomography/computed tomography (PET/CT) which specifically transported into cancer cells by L-type amino acid transporter 1 (LAT1). LAT1 overexpression in tumors is significantly correlated with cell proliferation and angiogenesis. (18)F-FAMT PET/CT, fluorine-18-fluorodeoxyglucose ((18)F-FDG) PET/CT and magnetic resonance imaging (MRI) were compared for their diagnostic performance in the detection of bone marrow invasion in patients with oral squamous cell carcinoma (OSCC)., Methods: Twenty-seven patients with OSCC on the upper or lower alveolar ridge underwent staging by MRI, (18)F-FDG PET/CT and (18)F-FAMT PET/CT studies before surgery. Post-surgical pathologic examination was used as the standard to determine the final diagnoses. The possibility of bone marrow invasion on MRI, (18)F-FDG PET/CT and (18)F-FAMT PET/CT were usually graded retrospectively into five-point score. Sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated according to the obtained scores., Results: As the sensitivity of (18)F-FDG PET/CT was highest (100 %) among that of MRI (95 %) and (18)F-FAMT PET/CT (90 %), the specificity of (18)F-FAMT PET/CT was highest (85.7 %) among that of MRI (57 %) and (18)F-FDG PET/CT (14.3 %). The size of pathological tumor was accorded with that detected by (18)F-FAMT PET/CT and was smaller than that detected by (18)F-FDG PET/CT (P < 0.01). Significant difference was not found between (18)F-FAMT PET tumor volume and pathological tumor volume., Conclusions: (18)F-FAMT PET/CT was useful and more specific than MRI or (18)F-FDG PET/CT in the detection of bone marrow invasion of OSCC and may contribute to minimize the extent of resection in oral surgery patient.

The pectoralis major musculocutaneous (PMMC) flap was once considered the workhorse for head and neck reconstruction; however, because of the proliferation of free tissue transfer, it has rightly taken on a secondary role. Nevertheless, in certain head and neck reconstructions, the PMMC flap remains the last-line treatment and the only salvage option in do-or-die scenarios. The conventional harvesting method of the PMMC flap cuts the lateral thoracic artery and all intercostals branches from the internal mammary vessel to avoid compromising pedicle length. Nonetheless, the dissection of these 2 dominant sources of blood supply to skin islands overlying the lower PMMC flap poses a potentially high risk of distal flap necrosis.To preserve the lateral thoracic vessels, the PMMC flap is a very valid choice from the viewpoint of blood supply. In a novel surgical procedure named "Supercharged Pectoral Major Musculocutaneous Flap"-"SUP-PMMC flap"-devised by us, the lateral thoracic vessels near the bifurcation of subclavian vessels are cut and then anastomosed to the cervical vessels. The procedure causes no vascular insufficiency of skin islands and no compromise to the length of the pedicle and is valid from the viewpoint of blood supply to the lower part of PMMC flaps. The author used this technique in 4 head and neck cancer reconstructions, and no partial flap necrosis or fistula formation was observed.

Previous work from our laboratory has demonstrated overexpression of chemokines in head and neck cancer and the utility of targeting these proteins for tumor therapy in a preclinical model. However, the mechanisms involved are unexplored. Through gene expression analysis, we found that expression of vascular endothelial growth factor (VEGF-C) was elevated in HN12 cells expressing high levels of CXCL5. In the present study, we have investigated the contribution of VEGF-C to tumor cell growth and motility. RNAi-mediated knockdown of VEGF-C expression in HN12 cells, which express high levels of CXCL5, resulted in a decrease in proliferation. Conversely, forced expression of VEGF-C in HN4 tumor cells with low endogenous CXCL5 levels increased cell growth. Suppression of VEGF-C inhibited migration of HN12 cells. Similarly, HN4 cells showed reduced migration towards conditioned media collected from HN12 cells with VEGF-C knockdown compared to controls, while HN4/VEGF-C conditioned media stimulated cell migration. Moreover, tumor growth in vivo was markedly reduced when VEGF-C expression was blocked by shRNA. Finally, determination of VEGF-C expression in squamous carcinoma cell lines revealed universal overexpression compared to normal keratinocytes. These findings support a role for VEGF-C in head and neck squamous cell carcinogenesis., (Copyright 2010 Elsevier Ltd. All rights reserved.)

We have investigated the role of the signaling intermediate, EPS8, in tumor progression using a model system and in vivo. HN4 primary tumor cells express low levels of EPS8, similar to normal keratinocytes, and show minimal invasion in vitro in response to epidermal growth factor, whereas HN12 cells express high levels of EPS8 and are highly motile in vitro and tumorigenic in vivo. Additional independent tumor cell lines also showed elevated EPS8 expression compared with normal keratinocytes. Using retroviral transduction, we generated HN4 cell lines expressing EPS8 (HN4/EPS8) at levels equivalent to those present in HN12 cells. HN4/EPS8 cells showed increased proliferation and migration compared with controls, together with elevated expression and activity of matrix metalloprotease (MMP)-9, which was dependent on protein kinase B (AKT) activity. Introduction of plasmids that direct synthesis of EPS8 short hairpin RNA (shRNA) into HN12 cells resulted in decreased EPS8 expression in these cells, which correlated with a decrease in their capacity to migrate and invade in vitro. In addition, shRNA-mediated knockdown of EPS8 reduced expression and activity of MMP-9 produced by these cells and reduced MMP-9 promoter activity. EPS8 knockdown cells showed decreased tumorigenicity in vivo compared with controls and lower MMP-9 expression. Conversely, overexpression of EPS8 in HN4 cells was sufficient to induce growth of these non-tumorigenic cells in orthotopic transplantation assays. Furthermore, EPS8 expression in clinical samples of squamous cell carcinoma showed variable expression levels and broadly paralleled expression of MMP-9. The data support a role for EPS8 in squamous carcinogenesis.

Previous work from our laboratory has demonstrated overexpression of chemokines in head and neck cancer, and the utility of targeting CXCL5 for tumor therapy in a preclinical model. In the present study, we investigated the contribution of a related chemokine, CXCL8, to cellular properties associated with tumor progression, namely cell growth and motility. Expression of CXCL8 was detectable in multiple squamous carcinoma cell lines, indicating a possible role in pathogenesis. Overexpression of CXCL8 in HN4 primary tumor cells with low endogenous CXCL8 levels was found to increase cell growth, as judged by cell counting and MTT assays. Conversely, RNAi-mediated knockdown of CXCL8 expression in HN12 cells, derived from a synchronous metastasis and which express high levels of this chemokine, resulted in a decrease in proliferation. Similarly, overexpression of CXCL8 enhanced migration of HN4 cells, while suppression of CXCL8 inhibited HN12 cell migration and invasion through a basement membrane substitute. Taken together, these findings support the hypothesis that CXCL8 affects multiple processes involved in tumor progression and identify CXCL8 as a potential therapeutic target, similar to CXCL5.

The biological properties of squamous carcinoma cells are intimately regulated by a multitude of cytokines and growth factors; the most well studied of these include epidermal growth factor receptor agonists and members of the transforming growth factor-beta family. The recent explosion of research in the field of chemokine function as a mediator of tumor progression has led to the possibility that these small, immunomodulatory proteins also play key roles in squamous carcinogenesis and may, therefore, be potential targets for novel therapeutic approaches.

We report a novel role for the CXC-chemokine, CXCL5, in the proliferation and invasion of head and neck squamous cell carcinoma (HNSCC). Previously, we reported transcriptional up-regulation of CXCL5 in metastatic cells. In this study, we provide biological validation of these findings and show that CXCL5 is intimately involved in tumor cell proliferation, migration, and invasion. Cells derived from a lymph node metastasis, but not from a synchronous primary tumor, secreted CXCL5 as judged by Western blotting of conditioned media. We used RNA interference to generate cell lines (shL5) in which CXCL5 expression was greatly reduced, and tested whether this modulated the cell phenotype. shL5 cells showed decreased proliferation compared with cells harboring nontargeting control sequences. In addition, we found that the ability of shL5 cells to migrate and invade in vitro through a basement membrane substitute was greatly impaired compared with control cells. Finally, whereas control cells were highly tumorigenic in nude mice, the tumorigenic potential in vivo of shL5 cells was found to be ablated. Taken together, these data suggest that CXCL5 production contributes to both enhanced proliferation and invasion of squamous cell carcinomas and that targeting of chemokine pathways may represent a potential therapeutic modality for these lesions.

Polypeptide growth factors play key roles in the processes of cell migration and invasion. In this study, we have used cDNA microarrays to identify target genes whose expression is differentially modulated by the growth factors TGFbeta and EGF. HN4 and HN12 cell lines, established from primary tumor and a lymph node metastasis arising in one patient with head and neck squamous cell carcinoma, were treated with 2nM EGF or 50pM TGFbeta for 24h and extracted RNA was used to prepare labeled cDNAs which were hybridized to NCI UniGem 2.0 cDNA microarrays containing 9128 features. Results revealed constitutive overexpression of 41 genes and underexpression of 109 genes in metastatic HN12 compared to HN4 under conditions of serum withdrawal. Furthermore, TGFbeta treatment resulted in relative upregulation of 53 genes and downregulation of 91 genes in HN12 compared with HN4, whereas cells treated with EGF showed relative upregulation of 67 genes and downregulation of 113 genes. Partial overlap was found between TGFbeta and EGF-modulated gene sets. Results were verified for a subset of each category using quantitative PCR, western blotting and zymography. The data indicate that TGFbeta and EGF differentially affect gene expression in primary and metastatic HNSCC cells, and likely contribute to the invasive properties of metastatic cells through regulation of both common and specific mediators for each growth factor.

Cell lines pairs were established from a primary squamous carcinoma of tongue and a lymph node metastasis and their biological behavior characterized. HN12 cells, derived from metastatic SCC, formed tumors upon subcutaneous transplantation to athymic mice, whereas HN4, derived from a primary lesion in the same individual, were non-tumorigenic in this assay. EGF stimulated proliferation of HN4 cells; in comparison, not only were metastatic HN12 cells refractory to the stimulatory effects of this growth factor but showed inhibition at higher growth factor concentrations. However, in contrast to the effects on proliferation, EGF (10 ng/ml) readily induced HN12 cells to invade in Boyden chamber assays whereas HN4 were non-invasive under these conditions. The invasive properties of HN12 cells were apparently independent of MMP-2 activity, as levels of active MMP-2 were higher in the non-invasive cells. However, EGF stimulated MMP-9 activity in invasive cells. Additionally, HN12 cells expressed constitutively high levels of active MMP-7 and MMP-3/10. The pharmacological agents LY294002, PD098059, SP600125, or SB202190 inhibited invasion of HN12 cells, suggesting requirement for phosphoinositide 3-OH kinase- and mitogen activated protein kinase-dependent pathways in the process. The data indicate that distinct biochemical differences distinguish metastatic squamous carcinoma cells from those derived from corresponding primary tumors, resulting in their contrasting biological properties.

Objective: N-Acetylglucosaminyltransferase V (GnT-V) is a key enzyme in the formation of branching asparagine-linked oligosaccharides and is linked to tumor invasion and metastasis in colon and breast cancers. In normal esophageal epithelium, beta1,6-branched asparagine-linked oligosaccharides synthesized by GnT-V are seen in the basal cell layers but not in the superficial cell layers, and its presence has been shown in invasive esophageal cancers. However, neither GnT-V expression nor its clinical significance has been previously examined in human normal, premalignant and malignant esophageal tissues., Methods: GnT-V expression was studied by immunohistochemistry using a specific monoclonal antibody in 121 surgically resected specimens of esophageal squamous cell carcinomas (SCCs) and adjacent tissues, and was analyzed statistically in relation to various characteristics., Results: GnT-V expression was observed in none (0%) of the 19 normal epithelial tissues, 1 (2%) of the 43 hyperplastic tissues, 30 (54%) of the 56 mildly dysplastic tissues, 27 (63%) of the 43 moderately dysplastic tissues, 21 (44%) of the 48 in situ SCCs and 29 (26%) of the 110 invasive SCCs (p<0.005). GnT-V expression was observed significantly more frequently in mildly and moderately dysplastic tissues when compared with normal epithelial and hyperplastic tissues (p<0.005), and its frequency was decreased in in situ and invasive SCCs (p<0.005). GnT-V expression was frequently observed in SCCs of small size and without distant metastasis or lymph node metastasis., Conclusions: Increased expression of GnT-V is associated with the early event of esophageal tumorigenesis., (Copyright (c) 2005 S. Karger AG, Basel.)

Purpose: Cyclophosphamide (CPA) has been shown to be quite effective and safe in the treatment of leukemia, but it had shown almost no efficacy in the treatment of solid tumors such as head and neck cancers. The purpose of this study was to determine whether head and neck squamous cell carcinomas can be made more sensitive to the cytotoxic effect of CPA by shifting the balance from the degradative to the activation pathway., Materials and Methods: Human SCC-25 squamous carcinoma cells were transfected by adenoviral vector containing P-450 2B1 gene and were identified for P-450 2B1 expression by Northern blot analysis. In vitro cytotoxic assay after CPA exposure was performed using these cells. Human KB oral base squamous cell carcinoma cells were injected subcutaneously to the backs of nude mice. Then Ad.CMV-P-450 2B1 was injected intratumorally. At 48 hours after the injection of Ad.CMV-P-450 2B1, CPA was injected into the peritoneal cavity of the animals and the volume of the tumor was determined with the passage of time. All the animal procedures were performed under the guidance of the committee in our animal care facility., Results: The in vitro experiments found that transduction of the P-450 2B1 gene caused a nearly 30-fold increase in the sensitivity of the host cell line to CPA on the basis of the 50% inhibitory concentration. The in vivo experiments, which were conducted in nude mice, found that the combination of P-450 2B1 gene transduction and administration of CPA showed an inhibitory effect on tumor growth., Conclusions: The P-450 2B1- cyclophosphamide system may be useful approach for gene therapy of squamous cell carcinomas of head and neck.

Background: Cytarabine is the most effective agent known for the treatment of acute myeloid leukemia. Its antitumor effect is expressed by combining with DNA during replication and then destroying the DNA chain. However, cytarabine has only limited activity against most solid tumors, including squamous cell carcinoma of the head and neck. The reason for this is thought to be that in cell lines of solid tumors the expression of cytidine deaminase, an enzyme that degrades cytarabine, is high, whereas the expression of deoxycytidine kinase (dCK), which phosphorylates cytarabine (a prodrug), is weak., Objective: To determine whether head and neck squamous cell carcinomas can be made more sensitive to the cytotoxic effects of cytarabine by shifting the balance from the degradative to the activation pathway., Methods: Human SCC-25 squamous carcinoma cells were transfected by either retroviral vector or adenoviral vector containing DCK gene and were identified for dCK expression by Northern blot analysis. In vitro cytotoxic assay after cytarabine exposure was performed using these cells., Results: Both retroviral and adenoviral vector-mediated transduction of the dCK complementary DNA resulted in marked sensitization of tongue squamous carcinoma cell lines to the cytotoxic effects of cytarabine in vitro., Conclusion: The dCK-cytarabine system may be a useful approach for gene therapy of squamous cell carcinomas of the head and neck.

The metastasis suppressor activity of nm23/nucleoside diphosphate (NDP) kinase was assessed using human oral squamous cell carcinoma (SCC) cell lines. When the expression of nm23/NDP kinase was compared among several SCC cell lines, nm23-H2/NDP kinase B gene product, but not nm23-HI/NDP kinase A gene product, was reduced in the metastatic cells. Transfection of nm23-H2 into the metastatic SCC cell line LMF4 caused reduction in the lung metastasis in an experimental metastasis assay. A histological analysis of the pulmonary metastatic foci revealed that although foci of the control clones were composed of anaplastic squamous cells, those of the nm23-H2-transfected clones consisted of mostly well-differentiated cells mimicking normal stratified epithelial constitution. The transfected cells were morphologically indistinguishable from the control ones in culture, but they differed from each other in that the former cells proliferated faster than the latter, became less serum dependent, and lost responsiveness to growth factors such as platelet-derived growth factor, insulin-like growth factor I, and insulin, although both clones retained sensitivity to transferrin. These results demonstrate that nm23-H2 protein does have metastasis suppressor activity for human SCC cells and suggest that this activity may be elicited by modulating growth and/or differentiation potential in response to environmental factors.

The nm23, encoding a protein identical to nucleoside diphosphate (NDP) kinase, is thought to be a candidate metastasis suppressor gene. Low expression of nm23 at the protein or/and mRNA levels was associated with metastatic potential of several types of rodent and human tumors. Expression and anti-metastatic action of nm23/NDP kinase gene products of human head and neck cancer (squamous cell carcinoma) cell lines were investigated. Among six cell lines examined, only those which showed metastatic potential exhibited reduced levels of nm23-H2 protein with no apparent change in nm23-H1 protein levels as compared with non-metastatic cells. When either nm23-H1 or nm23-H2 cDNA was transfected into a high metastatic cell line, only cell clones expressing higher levels of nm23-H2 protein above control levels displayed a reduced number of lung foci in an experimental metastasis assay. The data suggested that nm23-H2 gene product possesses the metastasis suppressor activity in human head and neck cancer cells.

We have established three cell lines (IMC-2, IMC-3, and IMC-4) from a human maxillary tumor, which exhibited different sensitivities to epidermal growth factor (EGF). It was inhibitory to colony-forming abilities of IMC-3 and IMC-4 cells in culture, while it affected that of IMC-2 cells slightly if at all. The differential sensitivities to EGF among the three cell lines were reproducibly observed when several cell sublines were further established from tumors appearing in nude mice. Saturation-binding kinetics with 125I-EGF showed similar levels of EGF-binding activities among the three cell lines. However, IMC-2, IMC-3, and IMC-4 showed almost similar sensitivities to cisplatin. Autophosphorylation of EGF receptor in the presence of EGF proceeded at similar levels among the three cell lines. Tumor growth was followed in nude mice when IMC-2, IMC-3, and IMC-4 at 1 x 10(7) cells were inoculated. The IMC-2 tumors enlarged at much faster rates than the other two cell lines. The IMC-4 tumors showed very slow growth rates, and IMC-3 tumors enlarged at an intermediate rate. These data suggest that the maxillary tumor used comprised cell populations that differed in their growth behaviors in response to EGF.

In this study, we examine drug resistance and sensitivity in tumor cell lines cultured from a patient undergoing prolonged chemotherapy. Four serially established primary tumor cell lines (KKM-A, -B, -C, and -D) were cultured from a case of maxillary sinus carcinoma: KKM-A from the nontreated primary tumor; KKM-B from the residual tumor after chemotherapy with cisplatin (CDDP) and 5-fluorouracil (5-FU); KKM-C from the local tumor that recurred following complete remission with chemoradiotherapy (combination of 5-FU, vitamin A, and radiation); and KKM-D from a metastatic lymph node tumor after further chemotherapy with CDDP and peplomycin. The sensitivity of the four cell lines to CDDP, 5-FU bleomycin (BLM), carboquone (CQ), and colchicine was assessed according to the reduction in colony formation. The KKM-A cell line was very sensitive to CDDP, BLM, CQ, and colchicine, whereas the posttreatment cell lines were resistant to these four drugs. The resistant cell lines were probably selected as a result of chemotherapy and radiotherapy. The nontreated KKM-A cell line was naturally somewhat resistant to 5-FU. The 5-FU-resistance of the KKM-B, -C, and -D cell lines was reduced in that order, corresponding to their relative degree of treatment. The KKM-D cell line from the metastatic lymph node showed a different sensitivity from the KKM-B and -C cell lines from the primary site, suggesting a heterogeneity in drug sensitivity between primary and metastatic tumor cells.

An esophageal cancer patient with bilateral lungs and neck lymph nodes metastases received 24 mg of vincristine instead of vinblastine because of the similarity between the two names, and survived multiorgan derangement. Serious states of central and peripheral neuropathy with muscle atrophy, gastrointestinal disorder, bone marrow suppression and mucocutaneous involvement were all encountered. Although hypotension and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) were not observed as vincristine's side actions, toxicity to the myocardium, which has not been documented, was suggested in our case. These toxic impairments, however, subsided clinically within a month, except for paresthesia in the peripheral extremities. The effectiveness of the chemotherapy was remarkable against both the esophageal cancer and the metastatic lesions. No unintentional overdose of a drug, needless to say, should happen, and in order to minimize its possibility, it would be advisable for chemotherapy to be administered only by an experienced physician who is able to check the dose and concentration.