Central nervous system penetration and enhancement of temozolomide activity in childhood medulloblastoma models by poly(ADP-ribose) polymerase inhibitor AG-014699.

BACKGROUND: Temozolomide shows activity against medulloblastoma, the most common malignant paediatric brain tumour. Poly(ADP-ribose) polymerase (PARP) inhibitors enhance temozolomide activity in extracranial adult and paediatric human malignancies. METHODS: We assessed the effect of AG-014699, a clinically active PARP inhibitor, on temozolomide-induced growth inhibition in human medulloblastoma models. Pharmacokinetic, pharmacodynamic and toxicity assays were performed in tumour-bearing mice. RESULTS: Sensitivity to temozolomide in vitro was consistent with methylguanine methyltransferase (MGMT) and DNA mismatch repair (MMR) status; MGMT(+) MMR(+) D384Med cells (temozolomide GI(50)=220 µM), representative of most primary medulloblastomas, were sensitised fourfold by AG-014699; MGMT⁻ MMR(+) D425Med cells were hypersensitive (GI(50)=9 µM) and not sensitised by AG-014699, whereas MGMT(+) MMR⁻ temozolomide-resistant D283Med cells (GI50=807 µM) were sensitised 20-fold. In xenograft models, co-administration of AG-014699 produced an increase in temozolomide-induced tumour growth delay in D384Med xenografts. Consistent with the in vitro data, temozolomide caused complete tumour regressions of D425Med xenografts, whereas D283Med xenografts were relatively resistant. AG-014699 was not toxic, accumulated and reduced PARP activity ≥75% in xenograft and brain tissues. CONCLUSION: We show for the first time central nervous system penetration and inhibition of brain PARP activity by AG-014699. Taken together with our in vitro chemosensitisation and toxicity data, these findings support further evaluation of the clinical potential of AG-014699-temozolomide combinations in intra-cranial malignancies.

Molecular structure and activity toward DNA of baicalein, a flavone constituent of the Asian herbal medicine "Sho-saiko-to".

Baicalein (5,6,7-trihydroxyflavone, 1) is of interest because of its broad spectrum of biological activity. It is a constituent of the east Asian herbal remedy, "Sho-saiko-to". The 3D structure of 1 was determined using X-ray diffraction. The compound exists in an almost planar conformation with a C-2-C-1' bond distance of 1.476(5) A. Hydrogen-bonding interactions predominate in the crystal structure. The position of the three hydroxyl groups maximizes intramolecular hydrogen bonding, and each of the hydroxyl hydrogen atoms is a donor in a three-center hydrogen bond. The carbonyl oxygen, O-4, is an acceptor in an intramolecular hydrogen bond (with OH-5). Two molecules of 1 exist as hydrogen-bonded dimers related by inversion center (-x + 1, -y, -z + 1). O-4 is also an acceptor in an intermolecular hydrogen bond with OH-6. The planarity of the flavone framework is dependent on structural and/or electronic forces that stabilize the negative charge on the exocyclic oxygen atom, O-4. Compound 1, therefore, is planar in any situation where forces can stabilize the negative charge on O-4. Consistent with this, UV absorbance studies performed on 1-DNA complexes with varying concentrations of 1 strongly suggest intercalation of 1 within the double helix, followed by possible interstrand cross-links.