Activity In Several Malignancies Research Articles

In vitro inhibition of cytidine triphosphate synthetase activity by cyclopentenyl cytosine in paediatric acute lymphocytic leukaemia.

Cytidine triphosphate (CTP) synthetase is a key enzyme for the synthesis of cytosine (deoxy)ribonucleotides, catalysing the conversion of uridine triphosphate (UTP) into CTP, and has a high activity in several malignancies. In this preclinical study, the enzyme activity and mRNA expression of the enzyme and (deoxy)ribonucleotide concentrations were analysed in leukaemic cells of 57 children suffering from acute lymphocytic leukaemia (ALL). In addition, in vitro experiments were performed with the CTP synthetase inhibitor cyclopentenyl cytosine (CPEC). A significantly higher activity of CTP synthetase (6.5 +/- 3.9 nmol CTP/mg/h) was detected in ALL cells than in lymphocytes of healthy controls (1.8 +/- 0.9 nmol CTP/mg/h, P < 0.001) that was independent of white blood cell (WBC) count, blast percentage, age, gender or type of ALL. The enzyme activity was not correlated with the CTP synthetase mRNA expression. The activity of CTP synthetase in ALL cells compared with non-malignant CD34+ bone marrow controls (5.6 +/- 2.4 nmol CTP/mg/h) was not statistically different. In vitro treatment of ALL cells with CPEC induced a dose-dependent decrease of the CTP concentration. The lowest concentration of CPEC (0.63 microM) induced a depletion of CTP of 41 +/- 20% and a depletion of dCTP of 27 +/- 21%. The degree of CTP depletion of ALL cells after treatment with CPEC was positively correlated with the activity of CTP synthetase. The inhibition of CTP synthetase in situ was confirmed by flux studies using radiolabelled uridine. From these results, it can be expected that CPEC has a cytostatic effect on lymphoblasts of children with ALL.

Clinical phase II evaluation of paclitaxel in combination with cisplatin in metastatic or recurrent squamous cell carcinoma of the head and neck

Paclitaxel as single agent has shown marked activity in several malignancies. The aim of the present phase II trial was to determine the activity of paclitaxel/cisplatin in patients with metastatic or recurrent squamous cell carcinoma of the head and neck. 200 mg/m2 paclitaxel was administered over three hours followed by cisplatin (100 mg/m2), repeated every 22 days. Twenty-eight patients were entered and received a total of 99 cycles (median 2, range 1-6). All patients were evaluable for toxicity, and 25 for response. Hematologic toxicities included leukopenia CTC grade 3 in 13 patients, and grade 4 in five patients, neutropenia grade 3 in nine patients, and grade 4 in eight patients, grade 3 anemia and grade 2 thrombocytopenia in one patient each. Non-hematologic toxicities included hypotension grade 2 (six patients), grade 3 (four patients), and grade 4 (two patients). A decline in renal function was observed in 15 courses and 10 patients, leading to a median delay of 2.5 days. Neurosensory and neuromotor toxicity grade 1 were observed in 13 patients (grade 2: 12 patients; grade 3: one patient), myalgia grade 3 in one patient, asthenia grade 3 in two and grade 4 in one patient. Partial responses were observed in 12 patients for an overall response rate of 48% (95% CI: 28%-68%) with a median response duration of 6.5 months (range 1-10 months). Stable disease was observed in seven patients, of who two also had clinical benefit. Paclitaxel 200 mg/m2 administered over three hours combined with cisplatin 100 mg/m2 is an active regimen warranting further evaluation.

Interferons: Current status and future directions of this prototypic biological

As phase II trials with alpha interferon are nearing completion it is clear that they have anti-tumor activity in several malignancies. When compared to other drugs currently used for malignant disease, the level of activity suggests their ultimate usefulness in clinical practice. Some patients have manifested complete responses to interferon administration: others have had long-term sustained anti-tumor effect. In addition to their significant clinical activity, interferons are prototypic biologic response modifiers. In this role, the development of the interferons has provided a model for other biologicals which are currently entering phase I clinical trials. As a model for the clinical application of biologics in general and for the clinical use of specific protein molecules, interferons are fulfilling their substantial promise.