Formation of a covalent intermediate between alpha-chymotryspin and the B-chain of insulin during enzyme-catalyzed hydrolysis.

The reaction between alpha-chymotrypsin (EC 3.3.21.1) and the B-chain of bovine insulin was studied radiochemically, by using the 3 5S-labelled sulfo B-chain. After incubation at pH 8.0, interrupted by the addition of trichloroacetic acid, a radioactive product was isolated from the reaction mixture. The labelled product was eluted in parallel with the enzyme in gel chromatography, and its properties at different H+ concentrations indicated that chemically it was an ester, i.e. a covalent enzyme-substrate intermediate. No interaction between sulfo beta-chain and alpha-chymotrypsinogen or phenyl-methyl sulfonyl fluoride-inhibited alpha-chymotrypsin was obtained during identical conditions.

Phase I study of tauromustine administered in a weekly schedule.

Tauromustine was administered orally in weekly doses with interindividual dose escalation to patients with disseminated malignant melanoma. The dose in the first cohort of 6 patients was 20 mg/m2/week. The dose escalation was 5 mg/m2/week. The limit of tolerance was 55 mg/m2/week. 99 patients completed at least 8 weeks of treatment and eight dose levels were evaluated for toxicity. Reversible thrombocytopenia, and to a lesser degree leukopenia, were dose limiting. From a starting dose of 40 mg/m2/week, the long-term tolerated dose was 35 mg/m2/week, thus achieving a considerable increase of dose intensity without a significant increase of toxicity by employing this weekly schedule of tauromustine.

Preliminary analysis of combined treatment with prednimustine and 4'epidoxorubicin in advanced breast cancer.

In an effort to define a well-tolerated therapeutic regimen for advanced breast cancer, we have studied a combination of 4'epidoxorubicin, 50 mg/m2 IV on day 1, and prednimustine, 100 mg/m2 PO on days 3 to 7 given every 3 weeks. Twenty-nine patients have been entered, and 22 are presently evaluable for response. Median age of the evaluable patients is 62 (range, 36 to 77), and median performance status (SAKK) is 2. Five patients had received chemotherapy, 16 hormonal therapy, five radiation therapy, and five no prior therapy for advanced disease. Most patients were in a high-risk group, with dominant visceral metastatic sites in 19 out of 22 cases. We have observed eight partial responses, nine no changes, and five progressions. Median response duration is 6 months. It is too early to discuss median overall survival. Toxicity is evaluable in 27 patients who received at least one course with a full dose of chemotherapy. Hematologic toxicity has been low, with only four patients having leukocyte nadirs below 2000/mm3 and three patients with thrombocyte nadirs below 100,000/mm3. Major alopecia (requiring a wig) was observed in eight patients. Emesis (controlled by minor antiemetics) was reported in six cases. This well-tolerated regimen is active in advanced high-risk elderly breast cancer patients, but dosage might be too low for younger patients and nonpretreated patients.

A preliminary analysis of combination therapy with vincristine, adriamycin, and prednimustine (VAP) in advanced breast cancer: a phase II study.

Between March 1984 and May 1985, 29 patients with metastatic breast cancer and high-risk prognostic factors were treated with vincristine, 1.4 mg/m2 IV on day 1, Adriamycin, 40 mg/m2 IV on day 1, and prednimustine, 100 mg/m2 PO on days 3 to 7. Courses were repeated every 3 weeks. At the present time, 26 patients are evaluable for tumor response; 29 are evaluable for toxicity. Fourteen of 26 patients (53.8%) achieved a partial response lasting 2 to 9 months (median 5.5+). A complete response was not recorded. Ten of 26 patients (38.5%) had stable disease; two patients (7.7%) showed a primary tumor progression. Most common side effects were nausea, vomiting, and alopecia, all generally mild to moderate. Fourteen of 29 patients developed leukocytopenia, mainly of WHO grade 1; thrombocytopenia was registered in one patient only and a fall of hemoglobin in three patients only. In 15 patients, no hematologic toxicity occurred. These preliminary data suggest good antitumor activity and acceptable toxicity for vincristine-Adriamycin-prednimustine in patients with metastatic breast cancer.

Prednimustine (NSC-134087, Leo 1031) treatment of lymphocytic and lymphocytic-histiocytic lymphomas.

Nineteen patients with advanced lymphocytic or lymphocytic-histiocytic lymphomas were treated with Prednimustine (NSC-134087, Leo 1031). The median induction dose was 25 mg/m2 a day by mouth (range 11-42). Ten patients had previously received radiation or chemotherapy, or both. Four patients had a complete remission and eleven a partial remission. The median duration of remission was 12.5+ months for complete responders and 5 months for partial responders. Thirteen patients had a moderate myelosuppression. One patient had urticaria and pruritus and refused further treatment.

Comparison between continuous and intermittent administration of Estracyt in the treatment of carcinoma of the prostate.

Ninety-five patients with prostatic carcinoma, stages A-D and of all histological grades were randomized between a continuous and an intermittent treatment regimen of Estracyt (estramustine phosphate). 77 patients were evaluated (46 with continuous and 31 with intermittent therapy). Remissions were seen in 13 (28%) and (13%), respectively. Stable disease was recorded in 30 (65%) and 24 (77%), respectively. Progression experienced 3 (6%) and 3 (10%) respectively. 19% were unable to continue therapy due to intolerable gastrointestinal side effects (7 patients receiving continuous and 8 patients receiving intermittent therapy).

Treatment of chronic lymphocytic leukaemia and well-differentiated lymphocytic lymphoma with continuous low- or intermittent high-dose prednimustine versus chlorambucil/prednisolone.

Prednimustine, a new antitumour drug, is a chlorambucil ester of prednisolone. The present prospective randomized study compares the effect of continuous low-dose (B) and intermittent high-dose (C) prednimustine in previously untreated patients with progressive CLL and WDLL. The control group received continuous chlorambucil/prednisolone therapy (A). One hundred and eighteen patients, 88 CLL and 30 WDLL, were evaluable. Response to therapy (greater than 50% improvement) was noted in 61, 55 and 57% in groups A, B and C respectively. The difference was not statistically significant. Time to response, response duration and survival did not show any differences between the groups. Responding patients survived longer than patients with stationary and progressive disease. Median survival time was 72 months from diagnosis and 52 months from start of therapy, with no differences between the treatment groups. Toxicity of prednimustine was usually mild and similar to that of the two constituents. Treatment schedule C showed a slight advantage with regard to frequency of side effects. In conclusion, in this study the therapeutic effect of prednimustine was equal to that of its constituents administrated separately.