Evaluation of poly (ADP-ribose) polymerase inhibitor ABT-888 combined with radiotherapy and temozolomide in glioblastoma

This is the final version. Available from the publisher via the DOI in this record.Background: The cytotoxicity of radiotherapy and chemotherapy can be enhanced by modulating DNA repair. PARP is a family of enzymes required for an efficient base-excision repair of DNA single-strand breaks and inhibition of PARP can prevent the repair of these lesions. The current study investigates the trimodal combination of ABT-888, a potent inhibitor of PARP1-2, ionizing radiation and temozolomide(TMZ)-based chemotherapy in glioblastoma (GBM) cells.Methods: Four human GBM cell lines were treated for 5 h with 5 μM ABT-888 before being exposed to X-rays concurrently with TMZ at doses of 5 or 10 μM for 2 h. ABT-888′s PARP inhibition was measured using immunodetection of poly(ADP-ribose) (pADPr). Cell survival and the different cell death pathways were examined via clonogenic assay and morphological characterization of the cell and cell nucleus.Results: Combining ABT-888 with radiation yielded enhanced cell killing in all four cell lines, as demonstrated by a sensitizer enhancement ratio at 50% survival (SER50) ranging between 1.12 and 1.37. Radio- and chemo-sensitization was further enhanced when ABT-888 was combined with both X-rays and TMZ in the O6-methylguanine-DNA-methyltransferase (MGMT)-methylated cell lines with a SER50 up to 1.44. This effect was also measured in one of the MGMT-unmethylated cell lines with a SER50 value of 1.30. Apoptosis induction by ABT-888, TMZ and X-rays was also considered and the effect of ABT-888 on the number of apoptotic cells was noticeable at later time points. In addition, this work showed that ABT-888 mediated sensitization is replication dependent, thus demonstrating that this effect might be more pronounced in tumour cells in which endogenous replication lesions are present in a larger proportion than in normal cells.Conclusions: This study suggests that ABT-888 has the clinical potential to enhance the current standard treatment for GBM, in combination with conventional chemo-radiotherapy. Interestingly, our results suggest that the use of PARP inhibitors might be clinically significant in those patients whose tumour is MGMT-unmethylated and currently derive less benefit from TMZ. © 2013 Barazzuol et al.; licensee BioMed Central Ltd.European Union: European Community’s Seventh Framework Programm

Radiobiologically derived biphasic fractionation schemes to overcome the effects of tumour hypoxia

OBJECTIVE: As a fractionated course of radiotherapy proceeds tumour shrinkage leads to resolution of hypoxia and the initiation of accelerated proliferation of radioresistant cancer cells with better repair capacity. We hypothesise that, in tumours with significant hypoxia, improved tumour control could be achieved with biphasic fractionation schedules that either use acceleration after 3–4 weeks of conventional radiotherapy or deliver a higher proportional dose towards the end of a course of treatment. We conducted a modelling study based on the concept of biological effective dose (BED) comparing such novel regimens with conventional fractionation. METHODS: The comparator conventional fractionation schedule 70 Gy in 35 fractions delivered over 7 weeks was tested against the following novel regimens, both of which were designed to be isoeffective in terms of late normal tissue toxicity. 40 Gy in 20 fractions over 4 weeks followed by 22.32 Gy in 6 consecutive daily fractions (delayed acceleration) 30.4 Gy in 27 fractions over 4 weeks followed by 40 Gy in 15 fractions over 3 weeks (temporal dose redistribution) The delayed acceleration regimen is exactly identical to that of the comparator schedule over the first 28 days and the BED gains with the novel schedule are achieved during the second phase of treatment when reoxygenation is complete. For the temporal redistribution regimen, it was assumed that the reoxygenation fraction progressively increases during the first 4 weeks of treatment and an iterative approach was used to calculate the final tumour BED for varying hypoxic fractions. RESULTS: Novel fractionation with delayed acceleration or temporal fractionation results in tumour BED gains equivalent to 3.5–8 Gy when delivered in 2 Gy fractions. CONCLUSION: In hypoxic tumours, novel fractionation strategies result in significantly higher tumour BED in comparison to conventional fractionation. ADVANCES IN KNOWLEDGE: We demonstrate that novel biphasic fractionation regimens could overcome the effects of tumour hypoxia resulting in biological dose escalation

[(18)F]Fluoroethyltyrosine- positron emission tomography-guided radiotherapy for high-grade glioma

BACKGROUND: To compare morphological gross tumor volumes (GTVs), defined as pre- and postoperative gadolinium enhancement on T1-weighted magnetic resonance imaging to biological tumor volumes (BTVs), defined by the uptake of (18)F fluoroethyltyrosine (FET) for the radiotherapy planning of high-grade glioma, using a dedicated positron emission tomography (PET)-CT scanner equipped with three triangulation lasers for patient positioning. METHODS: Nineteen patients with malignant glioma were included into a prospective protocol using FET PET-CT for radiotherapy planning. To be eligible, patients had to present with residual disease after surgery. Planning was performed using the clinical target volume (CTV = GTV union or logical sum BTV) and planning target volume (PTV = CTV + 20 mm). First, the interrater reliability for BTV delineation was assessed among three observers. Second, the BTV and GTV were quantified and compared. Finally, the geometrical relationships between GTV and BTV were assessed. RESULTS: Interrater agreement for BTV delineation was excellent (intraclass correlation coefficient 0.9). Although, BTVs and GTVs were not significantly different (p = 0.9), CTVs (mean 57.8 +/- 30.4 cm(3)) were significantly larger than BTVs (mean 42.1 +/- 24.4 cm(3); p < 0.01) or GTVs (mean 38.7 +/- 25.7 cm(3); p < 0.01). In 13 (68%) and 6 (32%) of 19 patients, FET uptake extended >or= 10 and 20 mm from the margin of the gadolinium enhancement. CONCLUSION: Using FET, the interrater reliability had excellent agreement for BTV delineation. With FET PET-CT planning, the size and geometrical location of GTVs and BTVs differed in a majority of patients

Endothelium-derived endothelin-1

One year after the revelation by Dr. Furchgott in 1980 that the endothelium was obligatory for acetylcholine to relax isolated arteries, it was clearly shown that the endothelium could also promote contraction. In 1988, Dr. Yanagisawa’s group identified endothelin-1 (ET-1) as the first endothelium-derived contracting factor. The circulating levels of this short (21-amino acid) peptide were quickly determined in humans, and it was reported that, in most cardiovascular diseases, circulating levels of ET-1 were increased, and ET-1 was then tagged as “a bad guy.” The discovery of two receptor subtypes in 1990, ET(A) and ET(B), permitted optimization of the first dual ET-1 receptor antagonist in 1993 by Dr. Clozel’s team, who entered clinical development with bosentan, which was offered to patients with pulmonary arterial hypertension in 2001. The revelation of Dr. Furchgott opened a Pandora’s box with ET-1 as one of the actors. In this brief review, we will discuss the physiological and pathophysiological role of endothelium-derived ET-1 focusing on the regulation of the vascular tone, and as much as possible in humans. The coronary bed will be used as a running example in this review because it is the most susceptible to endothelial dysfunction, but references to the cerebral and renal circulation will also be made. Many of the cardiovascular complications associated with aging and cardiovascular risk factors are initially attributable, at least in part, to endothelial dysfunction, particularly dysregulation of the vascular function associated with an imbalance in the close interdependence of nitric oxide and ET-1