The recent success of antibody-drug conjugates (ADCs) in the treatment of cancer has led to a revived interest in microtubuledestabilizing agents. Here, we determined the high-resolution crystal structure of the complex between tubulin and maytansine, which is part of an ADC that is approved by the US Food and Drug Administration (FDA) for the treatment of advanced breast cancer. We found that the drug binds to a site on β-tubulin that is distinct from the vinca domain and that blocks the formation of longitudinal tubulin interactions in microtubules. We also solved crystal structures of tubulin in complex with both a variant of rhizoxin and the phase 1 drug PM060184. Consistent with biochemical and mutagenesis data, we found that the two compounds bound to the same site as maytansine and that the structures revealed a common pharmacophore for the three ligands. Our results delineate a distinct molecular mechanism of action for the inhibition of microtubule assembly by clinically relevant agents. They further provide a structural basis for the rational design of potent microtubuledestabilizing agents, thus opening opportunities for the development of next-generation ADCs for the treatment of cancer.drug mechanism | microtubule-targeting agents | X-ray crystallography

Antiproliferative treatment of patients with metastatic endocrine gastroenteropancreatic tumours (GEP) is based mainly on chemotherapeutic protocols whereby drug toxicity is a major handicap. Octreotide is the first choice in the control of hormone mediated symptoms.

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Both intermittent positive-pressure ventilation and bilevel provided similar oxygenation and ventilation during cardiopulmonary resuscitation. Chest compression synchronized ventilation elicited the highest mean arterial pressure, best oxygenation, and a normal mixed venous pH during cardiopulmonary resuscitation.

A prospective study was performed to determine the efficacy of octreotide (Sandostatin; SMS 201-995) 200 micrograms tid in controlling tumor growth. The study included 21 patients with metastasized endocrine GEP tumors: 6 gastrinomas, 8 carcinoid syndromes, 7 nonfunctioning tumors. Treatment was performed for 3 to 59 months (median 15 months). Evaluation of the response to octreotide was facilitated in 12 patients by a pretreatment observation period of 3 to 47 months (median 17 months) during which the natural growth behavior was determined. Based on the presence or absence of a control period prior to treatment, 5 patients were considered to be responders, 7 as questionable responders (no pretreatment phase available), and 9 as nonresponders. None of the 21 patients had documented shrinkage of the tumor mass. The most favorable response was tumor standstill. In all but one responder an escape to an initially favorable response occurred after 6 to 28 months (median 14 months). Proved inhibition of growth was paralleled by a reduction of serum and urine hormone parameters, whereas unaltered progression of tumor growth was observed also in the presence of hormone suppression. Tumor growth and hormone release was inhibited in the absence and presence of somatostatin receptors on the tumor. It is concluded that octreotide exerts a limited effect on metastatic GEP tumor growth. The evaluation of a response to octreotide is facilitated by an observation period prior to the drug that provides information on growth characteristics of the tumor. The presence of octreotide receptors does not predict the success of therapy.

The natural product L-783277 is a resorcylic lactone type covalent kinase inhibitor. We have prepared the 5 0 -deoxy analogue of L-783277 (1) in a stereoselective fashion. Remarkably, this analogue retains almost the full kinase inhibitory potential of natural L-783277, with low nanomolar IC 50 values against the most sensitive kinases, and it exhibits essentially the same selectivity profile (within the panel of 39 kinases investigated). In contrast, removal of both the 4 0 -and the 5 0 -hydroxyl groups leads to a more significant reduction in kinase inhibitory activity and so does a change in the geometry of the C7 0 -C8 0 double bond in 1 from Z to E. These findings offer new perspectives for the design of second generation resorcylic lactone-based kinase inhibitors.

One hundred and fifteen gastroenteropancreatic (GEP) patients with malignant endocrine tumours entered a prospective multicentre trial (12 patients with gastrinoma, 53 with carcinoid syndrome, 45 with nonfunctioning tumours and 5 with other endocrine GEP tumours) to determine the efficacy of 200 μg Sandostatin® t.i.d. in the control of tumour growth. This interim report describes the results in 85 patients. Thirty-four patients died, 14 before and 20 after the first follow-up investigation, indicating a ‘negative’ selection of patients included in the trial and suggesting that Sandostatin® is unable to prevent disease progression when it is far advanced. In the evaluation of 68 patients followed up for at least 3 months, partial regression was observed in 4.4%, stable disease in 50% and tumour progression in 45%. An initially favourable response occurred frequently, however, it was followed by a decrease in response, from 54.4% at 3 months to 38% at 12 months, for the whole group of patients. Proven inhibition of tumour growth was mirrored by suppression of serum and urine hormone parameters. It is concluded that Sandostatin exerts a beneficial effect on tumour growth in patients with metastatic endocrine GEP tumours. This beneficial effect decreases with time and is as yet unpredictable in the individual patient.

BackgroundGuidelines recommend mechanical ventilation with Intermitted Positive Pressure Ventilation (IPPV) during resuscitation. The influence of the novel ventilator mode Chest Compression Synchronized Ventilation (CCSV) on gas exchange and arterial blood pressure compared with IPPV was investigated in a pig model.MethodsIn 12 pigs (general anaesthesia/intubation) ventricular fibrillation was induced and continuous chest compressions were started after 3min. Pigs were mechanically ventilated in a cross-over setting with 5 ventilation periods of 4min each: Ventilation modes were during the first and last period IPPV (100% O2, tidalvolumes = 7ml/kgKG, respiratoryrate = 10/min), during the 2nd, 3rd and 4th period CCSV (100% O2), a pressure-controlled and with each chest compression synchronized breathing pattern with three different presets in randomized order. Presets: CCSVA: Pinsp = 60mbar, inspiratorytime = 205ms; CCSVB: Pinsp = 60mbar, inspiratorytime = 265ms; CCSVC: Pinsp = 45mbar, inspiratorytime = 265ms. Blood gas samples were drawn for each period, mean arterial (MAP) and centralvenous (CVP) blood pressures were continuously recorded. Results as median (25%/75%percentiles).ResultsVentilation with each CCSV mode resulted in higher PaO2 than IPPV: PaO2: IPPVfirst: 19.6(13.9/36.2)kPa, IPPVlast: 22.7(5.4/36.9)kPa (p = 0.77 vs IPPVfirst), CCSVA: 48.9(29.0/58.2)kPa (p = 0.028 vs IPPVfirst, p = 0.0001 vs IPPVlast), CCSVB: 54.0 (43.8/64.1) (p = 0.001 vs IPPVfirst, p = 0.0001 vs IPPVlast), CCSVC: 46.0 (20.2/58.4) (p = 0.006 vs IPPVfirst, p = 0.0001 vs IPPVlast). Both the MAP and the difference MAP-CVP did not decrease during twelve minutes CPR with all three presets of CCSV and were higher than the pressures of the last IPPV period.ConclusionsAll patterns of CCSV lead to a higher PaO2 and avoid an arterial blood pressure drop during resuscitation compared to IPPV in this pig model of cardiac arrest.