NCIC CTG IND.181: phase I study of AT9283 given as a weekly 24 hour infusion in advanced malignancies.

PURPOSE: AT9283 is a potent inhibitor of the mitotic regulators, Aurora-kinases A and B, and has shown anti-tumor activity in patients with solid and haematological malignancies. This phase I study assessed safety, tolerability, pharmacokinetic and pharmacodynamic properties of AT9283. PATIENTS AND METHODS: Patients with advanced, incurable solid tumors or non-Hodgkin's lymphoma received AT9283 as a continuous 24-hour infusion on days 1, 8 of a 21-day cycle. A 3 + 3 dose escalation design was used with a starting dose of 1.5 mg/m(2)/day. Pharmacokinetic samples were collected from all patients on cycle one, and pharmacodynamic samples were collected from 4 patients at the recommended phase II dose (RP2D). RESULTS: 35 patients were evaluable for toxicity and 32 were evaluable for response. AT9283 was well tolerated, with main toxicities being reversible dose-related fatigue, gastrointestinal disturbance, anemia, lymphocytopenia and neutropenia. The dose limiting toxicities were febrile neutropenia (two patients) and neutropenia with grade 3 infection (1 patient) at 47 mg/m(2)/day (established as the maximum tolerated dose). The RP2D was 40 mg/m(2)/day. Pharmacokinetic analyses showed AT9283 appeared to follow linear kinetics, with a mean elimination half-life of 8.2 h. Pharmacodynamic analyses showed no consistent or significant changes, but trends suggested evidence of AT9283 inhibition and anti-proliferative activity. One patient had partial response and four patients experienced RECIST stable disease (median 2.6 months). CONCLUSION: In this study, AT9283 was well tolerated. The RP2D is 40 mg/m(2)/day on days 1, 8 of a 21-day cycle. Ongoing AT9283 trials will assess efficacy and safety in solid and haematological cancers.

The importance of a dedicated patch test clinic.

BACKGROUND: A specialist patch test clinic was set up in April 1997 at the Department of Dermatology, South Infirmary-Victoria Hospital, Cork, Ireland. The number of batteries available was expanded from six to 21 and the routine testing of patients to their own products was introduced, as was prick testing for latex hypersensitivity. OBJECTIVES: To assess the impact of introducing this clinic on the detection of allergic contact dermatitis. METHODS: Patch test results for the first full year of operation of the clinic (1998) were compared with those in the year prior to setting it up (1996). RESULTS: Although the number of patients tested rose after the introduction of the new clinic, the difference was not significant as the number of new dermatology general referrals had also risen. Thirty-one of the 91 patients tested in 1996 had positive patch tests compared with 84 of 158 tested in 1998 (P = 0.0036). Eighteen allergens were detected in 1996 and 53 in 1998. Two patients were positive to their own products in 1996, compared with 12 in 1998 (P = 0.04). The commercial batteries were negative in four of these cases. Three cases of latex hypersensitivity were detected in 1998. CONCLUSIONS: The introduction of a specialist patch test clinic resulted in an increase in detected cases of allergic contact dermatitis. The larger range of batteries available and the more widespread testing of patients' own products were the principal factors involved.

Cryotherapy of viral warts: a sustained 10-s freeze is more effective than the traditional method.

BACKGROUND: Cryotherapy is a standard treatment for viral warts. Although textbooks recommend treating until there is a halo of ice around the wart (traditional freeze), many authors advocate more aggressive cryotherapy. There are no previously published studies assessing the efficacy of longer freezing times. OBJECTIVES: To compare the efficacy of the traditional freeze and a sustained 10-s freeze in the treatment of common viral warts with liquid nitrogen. METHODS: Patients attending a dedicated wart clinic were randomized to receive either a traditional freeze or a 10-s sustained freeze with liquid nitrogen delivered by a spray gun. Two hundred patients were recruited, 100 in each group. RESULTS: After five treatments, 49 patients in the 10-s freeze group were clear of warts (64% of non-defaulters) as compared with 31 (39%) of those in the traditional freeze group (chi2 = 6.7; P = 0.009). Seventy-four patients in the 10-s freeze group as compared with 59 in the traditional freeze group had either improved or cleared after five treatments (chi2 = 5.0; P = 0.02). Morbidity was significantly greater in the 10-s freeze group. Sixty-four patients suffered pain or blistering as compared with 44 in the traditional freeze group (chi2 = 10.8; P = 0.0045). Five patients were withdrawn from the 10-s freeze group because of pain as compared with one patient in the traditional freeze group. CONCLUSIONS: A 10-s sustained freeze is more effective in the cryotherapy of viral warts but carries a significantly greater morbidity in terms of pain and blistering.

Discovery of a novel Raf kinase inhibitor.

We discuss the biology of Ras signal transduction and the epidemiology of ras mutations in association with disease as a background for the development of a Raf kinase inhibitor, BAY 43-9006. Knowledge of Ras effector pathways has permitted genetic validation of numerous targets involved in the Ras signaling cascade. A key Ras effector pathway involves the kinase cascade RAF/MEK/ERK (MEK: MAP/ERK kinase; ERK: extracellular signal related kinase). Indeed, we present studies of cell lines stably expressing mutant MEK constructs, which point to Raf kinase as a target for therapeutics with selective anti-tumor activity. Finally, a small molecule drug discovery program based on inhibition of Raf kinase activity is outlined and the initial pre-clinical development process of the Raf kinase inhibitor BAY 43-9006 is discussed.

C3 toxin activates the stress signaling pathways, JNK and p38, but antagonizes the activation of AP-1 in rat-1 cells.

Lysophosphatidic acid (LPA) stimulates the c-Fos serum response element (SRE) by activating two distinct signal pathways regulated by the small GTPases, Ras and RhoA. Ras activates the ERK cascade leading to phosphorylation of the transcription factors Elk-1 and Sap1a at the Ets/TCF site. RhoA regulates an undefined pathway required for the activation of the SRF/CArG site. Here we have examined the role of the Ras and RhoA pathways in activation of the SRE and c-Fos expression in Rat-1 cells. Pertussis toxin and PD98059 strongly inhibited LPA-stimulated c-Fos expression and activation of a SRE:Luc reporter. C3 toxin completely inhibited RhoA function, partially inhibited SRE:Luc activity, but had no effect on LPA-stimulated c-Fos expression. Thus, in a physiological context the Ras-Raf-MEK-ERK pathway, but not RhoA, is required for LPA-stimulated c-Fos expression in Rat-1 cells. C3 toxin stimulated the stress-activated protein kinases JNK and p38 and potentiated c-Jun expression and phosphorylation; these properties were shared by another cellular stress agonist the protein kinase C inhibitor Ro-31-8220. However, C3 toxin alone or in combination with growth factors did not stimulate AP-1:Luc activity and actually antagonized the synergistic activation of AP-1:Luc observed in response to co-stimulation with growth factors and Ro-31-8220. These data indicate that C3 toxin is a cellular stress which antagonizes activation of AP-1 at a point downstream of stress-activated kinase activation or immediate-early gene induction.

Extensive unstable psoriasis--morbidity and medical management.

Over a 5 year period, from January 1988 to January 1993, 23 patients were admitted with extensive unstable psoriasis, 21 of whom had full case notes available. Over the study period these 21 patients required 45 admissions, the mean duration of each admission being 30.54 days. Those patients living more than 30 miles from our unit required almost twice as many admissions as the city group. In 77% of cases, a precipitating factor for the acute flare was identified, and in 53% of these the precipitating factor was iatrogenic related. These patients are prone to develop complications of which infection is the most common. The complexity of medical management was reflected in the number of cross consultations requested. These findings have implications for the optimal delivery of care to this important sub-group of psoriatics.