Simultaneous radiochemotherapy with paclitaxel in non-small cell lung cancer: a clinical phase I study.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is one of the most active single agents available for the treatment of non-small cell lung cancer (NSCLC), with reported response rates of 21% to 24%. Its observed radiosensitizing effect is attributed to its interruption of cell development at the G2/M phase of the cell cycle, when cells are most sensitive to the killing effects of ionizing radiation. This phase I study of paclitaxel and simultaneous radiation therapy in patients with previously untreated, locally advanced inoperable stage IIIA/B NSCLC was designed to determine the maximum tolerated paclitaxel dose, to define the safety and toxicity of this combined modality, and to obtain preliminary data on its activity. Patients received a fixed dose of radiotherapy (1.8 Gy/d, 5 days a week, in shrinking-field technique, for a total dose of 59.4 Gy) and concomitant chemotherapy with a 3-hour infusion of paclitaxel once weekly on day 1, initially at a dose of 45 mg/m2, for 3 weeks. This dose remained constant during study levels 1 to 3, with the number of weeks of treatment increasing to 5 and 7 at levels 2 and 3, respectively. At dose level 4, the paclitaxel dose was increased to 55 mg/m2 over 7 weeks. Of 22 NSCLC patients who entered the study, 18 are evaluable for toxicity and response. Responses included one complete and 10 partial remissions; the other seven patients had minimal improvement. The therapy was well tolerated; no severe adverse events were associated with paclitaxel or radiotherapy. This combined modality appears to be a practicable and effective treatment for NSCLC. The maximum tolerated paclitaxel dose has not yet been reached, and dose escalation is planned.

Paclitaxel and simultaneous radiation in locally advanced stage IIIA/B non-small cell lung cancer: a clinical phase I study.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is one of the most active single agents for the treatment of non-small cell lung cancer, with response rates of 21% to 24%. We present a phase I study with paclitaxel and simultaneous radiation in previously untreated, locally advanced, inoperable, stage IIIA/B non-small cell lung cancer. The aims of the study were to determine the maximum tolerated dose, define the safety and toxicity, and obtain preliminary data about the activity of the combined modality. Patients received a fixed dose of radiotherapy (1.8 Gy/d, 5 days a week for 6.5 weeks, for a total dose of 59.4 Gy) and concomitant chemotherapy with paclitaxel 45 mg/m2 days 1, 8, and 15 in level 1; days 1, 8, 15, 22, and 29 in level 2; and days 1, 8, 15, 22, 29, 36, and 43 in level 3. The paclitaxel dosage was increased to 55 mg/m2 on days 1, 8, 15, 22, 29, 36, and 43 in level 4. Paclitaxel was administered as a 3-hour continuous intravenous infusion. Dexamethasone, clemastine, and ranitidine were given for hypersensitivity prophylaxis. Twenty-two patients (18 men and four women) entered the study; their median age was 66.5 years (age range, 38 to 74 years). Disease stage was IIIA in six of 22 patients and stage IIIB in 16. Six patients were treated at level 1, five at level 2, five at level 3, and six at level 4. There were 18 patients evaluable for toxicity and response. Side effects generally were moderate during the treatment period. One patient withdrew by request after the first course, one patient died of tumor bleeding after five courses, one patient died of progressive disease (lymphangiosis carcinomatosa of both lungs) after the sixth course, and one patient is too early for evaluation. Among the 18 patients evaluable for response, there were one complete and 10 partial remissions; seven patients reached a minor response. It is concluded that the therapy was well tolerated in these patients. Importantly, no severe adverse events were observed that could be associated with paclitaxel or radiotherapy. This combined modality appears to be a practicable and effective treatment of non-small cell lung cancer. The maximum tolerated dose has not yet been reached, and dose escalation is planned.

A three-dimensional solubility parameter approach to nonaqueous enzymology.

Widespread commercial application of enzymes as catalysts for specialty or commodity chemical synthesis will require their use in nonaqueous systems. While a number of non-aqueous enzyme applications have been demonstrated, the lack of useful rules for predicting enzyme-solvent interactions has hindered the development of this technology. Both Hildebrand and solvent hydrophobicity (octanol-water partition coefficient) parameters have been used previously to correlate and predict enzyme activity in nonaqueous systems, with some success, but any single-parameter approach is inherently limited in its ability to reflect the spectrum of possible enzyme-solvent interactions. Therefore, this study evaluates the three-dimensional solubility parameter space, as proposed by Hansen, to correlate and predict enzyme activity in microaqueous, miscible, and biphasic nonaqueous systems. Preliminary results suggest that Hansen parameters may be useful for correlating nonaqueous enzyme activity, and that the dispersive and polar parameters may be disproportionately important in single-phase microaqueous systems. The Hansen hydrogen-bonding parameter appears to be the only parameter yet evaluated capable of correlating the water requirement for enzyme activity in microaqueous systems, suggesting that water affects protein structure through enthalpic rather than entropic processes in nonaqueous systems. Insufficient data are available for miscible and biphasic systems, but it is proposed that enzyme activity may correlate with the average solubility parameters of miscible systems and of the aqueous phase in biphasic systems.