BackgroundSagopilone, the first fully synthetic epothilone, has shown promising preclinical activity in tumour models. This open-label randomised phase II study investigated two infusion schedules of sagopilone in women with ovarian cancer.Patients and methodsWomen with ovarian cancer recurring within 6 months of end of last platinum-containing treatment received sagopilone 16 mg/m2 as a 3- or 0.5-h i.v. infusion every 21 days for up to 6 weeks.ResultsSixty-three patients received sagopilone as a 3-h (n = 38) or 0.5-h (n = 25) infusion. There were nine confirmed tumour responses [by modified RECIST (n = 8) and by Gynecologic Cancer Intergroup CA-125 criteria (n = 1)] in 57 patients assessable for efficacy overall [three (13%) with 0.5-h and six (18%) with 3-h infusions]. The 0.5-h arm was closed when it failed to meet its target efficacy. Main drug-related adverse events were peripheral sensory neuropathy (73%; 16% grade 3), nausea (37%; 2% grade 3), fatigue (35%; 3% grade 3) and arthralgia (30%; 5% grade 3). Overall incidence of peripheral sensory neuropathy was similar in both treatment arms, with no grade 4 neuropathy events. No acute allergic infusion reactions were observed.ConclusionSagopilone is effective, with balanced tolerability, in patients with recurrent platinum-resistant ovarian cancer.

5033 Background: BAY 73–4506 is an orally active, potent multikinase inhibitor targeting both tumor cell proliferation and tumor vasculature through inhibition of receptors of tyrosine kinases (VEGFR, KIT, RET, FGFR, and PDGFR) and serine/threonine kinases (RAF and p38MAPK). In tumor xenograft models, BAY 73–4506 demonstrated a broad spectrum of antitumor activity. The results of a phase I study (3 weeks on/1 week off schedule) indicated good tolerability and antitumor activity, including objective responses. Methods: Previously untreated patients with predominantly clear cell renal cell carcinoma (RCC) and measurable disease according to RECIST were enrolled in this multicenter, open-label, phase II study. Eligibility criteria included ECOG performance status 0–1, low or intermediate risk as per Motzer score, and adequate bone marrow and organ function. Treatment consisted of BAY 73–4506 160 mg once daily on a 3 weeks on/1 week off schedule. The primary end point was overall response rate. Results: 49 patients started treatment (accrual completed October 2008): 27 male, 22 female, median age 62 years (range 40–76). All patients were evaluable for safety, 33 patients are currently available for efficacy evaluation. The most common drug-related adverse events (all grades) reported in >20% of patients were hand-foot skin reaction (HFSR) (48%), fatigue (48%), hypertension (43%), mucositis (35%), dysphonia (33%), rash (30%), diarrhea (25%), and anorexia (23%). Grade 3–4 drug related toxicities (in >5% of patients) included HFSR (13%), rash (8%), fatigue (8%), and renal failure (8%). Renal failure occurred only in patients who continued taking study medication despite having inadequate fluid intake and/or diarrhea. Preliminary efficacy data of the 33 patients evaluable for response show a 27% partial response (PR) and a 42% stable disease (SD) rate. Further tumor assessments are scheduled for the patients (n = 35) remaining on study. Conclusions: Preliminary data show promising antitumor activity and good tolerability of BAY 73–4506 in patients with RCC. The observed toxicities were typical of the drug class and were manageable. Updated results will be presented at the meeting. [Table: see text]

Beam-column elements may be tapered in several ways and as the result their deflection shapes can be quite different. In this paper the finite beam elements with the linearly changing sections are studied. The changing properties of the commonly seen sections such as rectangular, circular and tubular sections as well as the complex thin-walled sections are derived. Based on the characteristics of their algebra formulations the tapered beams are identified in five categories. By analysing the deflection shapes under various boundary conditions the shape function matrices and their derivative matrices in four categories are formed. These matrices can be effectively used in the development of the tapered beam elements.

Hintergrund: Das vollsynthetisch hergestellte Epothilon ZK-Epo hat signifikante präklinische Aktivität bei humanen Lungenkarzinom-Zelllinien gezeigt. In einer nachfolgenden Phase I Studie wurde ZK-EPO gut vertragen und Tumorremissionen wurden beobachtet. Die Hauptnebenwirkung in dieser Studie war periphere Neuropathie. In der hier vorgestellten Phase II Studie erfolgte die Prüfung der Wirksamkeit und Sicherheit von ZK-EPO bei vorbehandelten Pat mit fortgeschrittenem NSCLC (Stadium IIIB/IV).

We determined the cytotoxic effects BMS 247550 (Epo B), a derivative of epothilone B, on cisplatinum- or paclitaxel-sensitive or -resistant human ovarian cancer cells. Additionally, we determined the effect of Epo B on Apo-2L/TRAIL-induced apoptosis of ovarian cancer cells.Epo B-induced cytotoxic and cell cycle effects were evaluated by the MTT assay and flow cytometry, respectively. Epo B-induced apoptosis was assessed by immunoblot analyses of the processing and proteolytic activity of caspases, flow cytometric measurement of annexin V staining, and the TUNEL assay. The effects of Epo B and/or Apo-2L/TRAIL on the protein expressions of the death receptors DR4 and DR5 as well as of XIAP and survivin were determined by immunoblot analyses.In the cell cycle-synchronized ovarian cancer cells, Epo B induced tubulin polymerization and mitotic arrest, followed by apoptosis. This was associated with the cytosolic accumulation of cytochrome (cyt) c and Smac/DIABLO as well as PARP cleavage activity of caspase-3. Epo B was able to exert cytotoxic effects against cisplatinum- and paclitaxel-resistant ovarian cancer cells. Epo B increased the expressions of DR4 and DR5, as well as augmented Apo-2L/TRAIL-induced processing of caspase-8 and Bid. This was associated with more caspase-3 activity, a decline in the intracellular levels of XIAP, cIAP, and survivin, and apoptosis of ovarian cancer cells.These data support the in vivo testing of Epo B against cisplatinum- and paclitaxel-resistant ovarian cancers, and suggest that a pretreatment with Epo B may sensitize human ovarian cancers to the cytotoxic effects of Apo-2L/TRAIL.