Reduction of in vivo tumor growth by MMI-166, a selective matrix metalloproteinase inhibitor, through inhibition of tumor angiogenesis in squamous cell carcinoma cell lines of head and neck.

Matrix metalloproteinases (MMPs) have been implicated in tumor invasion, metastasis, and angiogenesis. We have recently shown that MMI-166, a new orally active MMP inhibitor specific for MMP-2 and -9, suppressed experimental metastasis of Lewis lung cancer, C-H1 human colon cancer, and pancreatic cancer without affecting tumor growth in vitro. In the present study, we determined whether oral administration of MMI-166 reduces tumor growth not only in such tumors but also in squamous cell carcinoma of head and neck (SCCHN). MMI-166 inhibited both activity of MMP-2 and -9 without affecting steady state levels of their mRNAs in SCCHN. Interestingly, protein levels of MMP-2 and -9 from the cultures were drastically diminished by culturing with MMI-166. This was also observed in xenografts of MMI-166-administered mice. In addition, daily oral administration of MMI-166 (100mg/kg) inhibited local tumor growth accompanied by the reduction of blood vessel density and Ki-67-positivity and increase in terminal deoxynucleotidyl transferase-mediated cUDP nick-end labeling (TUNEL)-positivity. These results suggested that orally administered MMI-166 reduced in vivo tumor growth of SCCHN through inhibition of angiogenesis and induction of apoptosis accompanied by the reduction of MMP productions and activities. Therefore, MMI-166 seems to be useful for tumor dormancy therapy of SCCHN.

[Two head and neck cancer patients who responded to chemotherapy consisting of only TS-1].

We report two head and neck cancer patients who responded to TS-1. Case 1, a 52-year-old man was admitted to our department a diagnosis of supraglottic laryngeal cancer (T3N2cM0) on January 25, 2000. Concurrent chemoradiotherapy consisting of 2 courses of chemotherapy and radiation therapy at 70.2 Gy was administered. After the treatment, a biopsy showed a remaining cancer in the primary lesion. Since the patient refused to undergo surgery, the patient was followed up at the outpatient clinic using UFT at 400 mg/day. Because pulmonary metastasis was detected by chest CT, administration of TS-1 was started. TS-1 was administered at the conventional dose of 120 mg/day for 4 weeks followed by a 2-week rest. According to a CT conducted after 2 courses, the mass in the lung field disappeared and the clinical outcome was judged to be a CR. The TS-1 administration is still continuing, and the patient's condition also remains a CR. Case 2 was a patient with highly-differentiated adenocarcinoma in the ethmoid sinus (T3N2bM0). The patient was inoperable and was given radiation therapy of 64.8 Gy. Because of no change of the tumor after radiotherapy, TS-1 was administered at 60 mg x 2/day for 4 weeks followed by a 2-week rest. After TS-1 was administered for 3 courses, a CT showed a remarkable regression of the tumor resulting in a PR for the primary and the neck lesion. Upper gastrointestinal endoscopy during the 4th course detected a gastric ulcer of the A1 stage, and the patient was immediately admitted to the hospital. The ulcer was an adverse reaction of grade 3, which was improved by conservative therapy. TS-1 was restarted with a dose of 100 mg/day on April 11. No particular adverse reaction has been observed since then. The patient has received 13 courses of TS-1 and is still receiving TS-1. No clear tumor has been observed, and the clinical outcome is considered to be a CR. TS-1 is considered to be an excellent oral anticancer drug in terms of its anti-tumor effect and the patient's QOL.

A study of the early stage of Dysphagia in amyotrophic lateral sclerosis.

In amyotrophic lateral sclerosis (ALS) patients, dysphagia eventually occurs independent of time of onset. We studied dysphagia conditions in the early stage of ALS, principally at the oral phase. Videofluoroscopic and manometric studies were conducted on 11 patients (5 males and 6 females, age range = 47-82 years) who were diagnosed at our Neurology Clinic as having ALS. All patients were able to ingest orally. Swallowing scores on the ALS severity scale were from 10 to 5. In the oral phase of swallowing, abnormal movements of the anterior and/or posterior tongue were recognized in 8 cases. Dysphagia severity tended to be particularly influenced by dysfunction of the posterior tongue. Manometric studies were almost normal in all cases except one. These results suggested that the early stage of dysphagia in ALS was mainly caused by oral dysfunction, and the oral phase disorders began in some cases with a decreased function of bolus transport at the anterior part of the tongue, and in other cases with a deteriorated function of holding the bolus at the posterior part of the tongue. In conclusion, the tongue function of holding the bolus in the oral cavity mainly affects the severity of the early stage of dysphagia in ALS.