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.butyl group within the lead molecule 1, to the corresponding d9-tert.butyl analogue 2, led to an increase in both the in vitro and in vivo metabolic stability. This increase in metabolic stability resulted in a 2-fold increase in the oral bioavailability measured in the rat, and a 3-fold increase in potency in a chronic in vivo study in the mouse, for 2 when compared to 1.

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 40 (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. A rationale for the poor tolerability profile of 40 in a clinical study is discussed.

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. Positive common iliac lymph nodes are associated with a poorer prognosis than positive pelvic lymph nodes excluding common iliac group. For radiation planning in patients with cervical cancer, lymph node regions at high risk for metastases have to be encompassed. Usually, standard fields are used with the upper field border on the fourth/fifth lumbar vertebra. The authors evaluated whether standard fields are sufficient for encompassing the common iliac lymph nodes. PATIENTS AND METHODS: Pretreatment computed tomographic (CT) images of 42 patients with cervical cancer were evaluated to locate the aortic bifurcation and the subsequent common iliac lymph drainage. Anatomy of the lymph drain was correlated with standard radiation portals. RESULTS: In 17/42 patients (40%) the aortic bifurcation lay superior to the upper field border. In an additional nine patients (21%) the bifurcation was located on the level of the upper field border. In 26/42 patients (62%) standard radiation fields encompassed the common iliac lymph nodes insufficiently. CONCLUSION: Common iliac lymph node metastases are found in up to 50% of patients with node-positive cervical cancer. The results of this study demonstrate an unsatisfactory coverage of the common iliac lymph drain by standard fields in most patients. Thus it is necessary to individualize the planning target volume and to include the whole common iliac vessels according to the patient's anatomy on radiation treatment planning CT in order to improve local control.

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. In contrast, we observed a pronounced 3- to 5-fold accumulation of this cytotoxic adduct exclusively in the marginal cells of the stria vascularis between 8 and 48 h after treatment with cisplatin. In the kidney, the other critical target tissue of cisplatin toxicity, a similar high preferential formation of cytotoxic DNA adducts was measured in the tubular epithelial cells but not in other renal cell types. As for the ear, this excessive formation of DNA damage in a particular cell type was seen in animals treated with cisplatin but not those treated with carboplatin. Because cisplatin ototoxicity is often attributed to oxidative stress mediated by the generation of radical oxygen species (ROS), we have measured in parallel the levels of the lead DNA oxidation product 8-oxoguanine (8-oxoG) in cochlear cryosections. Compared with basal levels in untreated control cochleas, no additional formation of 8-oxoG was detectable up to 48 h after cisplatin treatment in the DNA of either inner-ear cell type. This suggests that the generation of ROS may be a secondary event in cisplatin ototoxicity.

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. Structures most important for visual acuity (fovea and optic disk, optic nerve) were contoured identically for both therapies. Safety margins of 1.5 mm for proton therapy were reduced to 1.0 mm for SRT. RESULTS: Proton-beam therapy was superior in eight of ten situations, and this result did not differ significantly by changes in the weighting of the different parameters analyzed. CONCLUSION: When dose deposition to those structures most important for the preservation of vision is taken into account, under the conditions examined proton therapy offers an advantage in the majority of the patients evaluated.