Identification of NVP-CLR457 as an Orally Bioavailable Non-CNS-Penetrant pan-Class IA Phosphoinositol-3-Kinase Inhibitor.

Balanced pan-class I phosphoinositide 3-kinase inhibition as an approach to cancer treatment offers the prospect of treating a broad range of tumor types and/or a way to achieve greater efficacy with a single inhibitor. Taking buparlisib as the starting point, the balanced pan-class I PI3K inhibitor (NVP-CLR457) was identified with what was considered to be a best-in-class profile. Key to the optimization to achieve this profile was eliminating a microtubule stabilizing off-target activity, balancing the pan-class I PI3K inhibition profile, minimizing CNS penetration, and developing an amorphous solid dispersion formulation.

Increasing metabolic stability via the deuterium kinetic isotope effect: An example from a proline-amide-urea aminothiazole series of phosphatidylinositol-3 kinase alpha inhibitors.

In vitro metabolic identification studies with a PI3K-α inhibitor lead molecule 1 identified a single predominant site of oxidative metabolism to be occurring within a tert.butyl moiety. Modification of the tert.

High accumulation of platinum-DNA adducts in strial marginal cells of the cochlea is an early event in cisplatin but not carboplatin ototoxicity.

Ototoxicity is a typical dose-limiting side effect of cancer chemotherapy with cisplatin but much less so with carboplatin. To elucidate the underlying molecular pathological mechanisms, we have measured the formation and persistence of drug-induced DNA adducts in the nuclei of inner ear cells of guinea pigs after short-term exposure to either cisplatin or carboplatin using immunofluorescence staining and quantitative image analysis. After application of carboplatin, all cells of the cochlea exhibited a similar burden of guanine-guanine intrastrand cross-links in DNA.

Interindividual variability of lymph drainages in patients with cervical cancer. Implication on irradiation planning.

Background And Purpose: Lymph node metastases and the number of positive lymph nodes are important prognostic factors for patients with cervical cancer. The most important route is the lateral drainage via the obturator to the internal and external iliac and common iliac area. The risk for common iliac lymph node metastases is increased in patients with positive pelvic or paraaortic lymph nodes.

Proton or stereotactic photon irradiation for posterior uveal melanoma? A planning intercomparison.

Background And Purpose: Proton and stereotactic radiotherapy with photons (SRT) are both used to treat choroidal melanomas in proximity to optic disk and fovea centralis, a situation where plaque therapy is prone to complications. A comparative treatment- planning study was done to assess the capability of both modalities to preserve vision.

Patients And Methods: In ten patients treated with 68-MeV protons, SRT with 6-MV photons was planned.