Phase 2 study of T138067-sodium in patients with malignant glioma: Trial of the National Cancer Institute of Canada Clinical Trials Group

We studied the activity of T138067-sodium in patients with malignant gliomas. T138067-sodium is a unique new chemotherapy agent that inhibits microtubule formation by binding irreversibly and specifically to beta(1), beta(2)and beta(4) isotypes of 3-tubulin, causing cell arrest at G(2)/M and inducing apoptosis. Patients with recurrent anaplastic astrocytoma or glioblastoma multiforme were treated intravenously with 330 mg/m(2) of T138067-sodium weekly. Treatment was continued until the patient experienced either unacceptable toxicity or progressive disease. Patients had to have histologically proven glioma, have bidimensionally measurable disease at least 1 cm x 1 cm, and have received no more than one prior adjuvant chemotherapy. No chemotherapy or radiotherapy for recurrent disease was permitted. Nineteen patients entered the trial. One patient was found to be ineligible. There were two patients with anaplastic astrocytoma and 16 with glioblastoma multiforme. Only two patients had received prior adjuvant chemotherapy. The first seven patients had full pharmacokinetic sampling. No dose-limiting toxicity was seen, and pharmacokinetic results were consistent with those from nonglioma patients. The most common drug-related effects were fatigue (33%), nausea (28%), neutropenia (28%), and anorexia (17%). No patients stopped the study because of toxicity. No responses were seen in the 15 eligible patients who completed at least one cycle. Three patients had stable disease with a median duration of 2.6 months. Our results suggest that given in this dose and schedule T138067-sodium does not have activity in this population of anaplastic astrocytoma and glioblastoma multiforme.     

Increased matrix metalloproteinase-13 production with aging by human articular chondrocytes in response to catabolic stimuli

Chondrocyte anabolic activity has been shown to decline with aging, but catabolic activity has received little attention. In this study, the effect of aging on the chondrocyte catabolic response was determined by stimulating isolated human chondrocytes with fibronectin fragments (FN-f) or interleukin-1beta and measuring matrix metalloproteinase-13 (MMP-13) production as a catabolic response. A significant age-related increase in chondrocyte MMP-13 production was noted. FN-f stimulation of MMP-13 expression was blocked using a nuclear factor kappa-B (NFkappaB) inhibitor suggesting a role for NFkappaB in this chondrocyte catabolic response. Chondrocyte production of the NFkappaB-regulated cytokine interleukin-1beta was also found to increase with donor age in unstimulated cells. These results demonstrate a significant age-related increase in chondrocyte catabolic responsiveness which could contribute to the development of osteoarthritis in older adults.     

Cardiovascular effects of intracerebroventricular norepinephrine in conscious and anaesthetized monkeys.

Norepinephrine, infused into the third cerebral ventricle of 7 restrained, unanaesthetized rhesus monkeys, evoked dose-related increases in systemic arterial pressure at each of three different (30 sec, 5 min or 1 hr) infusion times and rates. Anaesthetic doses of sodium pentobarbital blocked, but did not reverse, the presser response. A series of 6-hydroxydopamine injections (31 mg over an 11-day period) given centrally to 3 monkeys led to a steady reduction of basal blood pressures and pulse rates (?18 and ?16 mm Hg systolic and diastolic and ?34 beats/min during the second week after the last injection) and blocked the effects of centrally, but not intravenously, administered norepine- phrine. The monkeys had intense sympathomimetic response to the initial injection of 1 mg of 6-hydroxydopamine, but became progressively tachyphylactic to subsequent higher doses. The results suggest that noradrenergic nerves near the lateral and third ventricles of primates play an important role in controlling both acute and chronic levels of systemic arterial blood pressure.