A phase I trial of radiotherapy and simultaneous 24-hour paclitaxel in patients with locally advanced head and neck squamous cell carcinoma.

Preclinical studies have demonstrated that tumor cells exposed to paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) for protracted periods (ie, 24 hours) and then irradiated undergo enhanced radiation-induced cell kill. Importantly, paclitaxel-induced tumor cell mitotic arrest at the time of radiation was associated with the enhanced cell kill. At the Case Western Reserve Cancer Center, we have conducted a phase I trial in 24 patients with either locally advanced or recurrent/metastatic head and neck squamous cell carcinoma to evaluate the clinical and pharmacologic effects of a 24-hour paclitaxel infusion combined with radiotherapy. The maximum tolerated dose was < or =75 mg/m2. Dose-limiting toxicity was febrile granulocytopenia. Mucositis was significant and necessitated the use of enteral feeding tubes in the majority of patients. All patients with locally advanced disease demonstrated either a complete response or major partial response. At a median follow-up of 13.4 months, disease has relapsed in only two of 22 patients with locally advanced disease. Pharmacokinetic studies revealed that a dose of > or =75 mg/m2 achieved near steady-state mean paclitaxel plasma concentrations greatly exceeding the threshold concentrations shown to alter microtubule function and induce tumor cell mitotic arrest in vitro. Pharmacodynamic studies performed at 21 to 26 hours after initiation of infusion demonstrated that a dose of > or =75 mg/m2 uniformly induced tumor cell mitotic arrest and oral epithelial mitotic arrest. The pharmacologic data and outcome results provide a strong rationale for the continued use of a 24-hour paclitaxel infusion and concurrent radiation for the treatment of newly diagnosed, locally advanced head and neck squamous cell carcinoma in an experimental setting.

Rabbit ileal brush-border membrane Cl-HCO3 exchanger is activated by an internal pH-sensitive modifier site.

The purpose of these studies was to look for evidence of a pH-sensitive modifier site on the Cl-HCO3 exchanger on the brush-border membrane in rabbit ileum utilizing membrane vesicles. When internal pH and HCO3 were increased, Cl uptake was stimulated in a sigmoidal fashion consistent with a modifier effect. Increasing internal HCO3 alone did not have a similar effect, and increasing pH alone in the absence of HCO3 resulted in very little uptake of Cl. These results suggested that OH was a poor substrate for the exchanger but that it "activated" the transport of HCO3. Further evidence for this hypothesis was provided by the observation that increasing internal pH also stimulated Cl-Cl exchange. Altering the membrane potential with K and valinomycin had no effect on Cl uptake at high internal pH, suggesting no change in the 1:1 coupling ratio for Cl-HCO3 exchange at high internal pH. These studies provide evidence that there is an internal pH-sensitive modifier site on the Cl-HCO3 exchanger.