Purpose: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888. Experimental Design: In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation. Results: ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with K i s of 5.2 and 2.9 nmol/L, respectively.The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d  10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity. Conclusions: ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.poly(ADP-ribose) polymerase (PARP)-1 is the founding member of a family of poly(ADP-ribosyl)ating proteins. All PARP family members are characterized by the ability to poly(ADP-ribosyl)ate protein substrates and all share a catalytic PARP homology domain (1). PARP-1 and the closely related PARP-2 are nuclear proteins and the only PARPs with DNA binding domains. These DNA binding domains localize PARP-1 and PARP-2 to the site of DNA damage serving as DNA damage sensors and signaling molecules for repair. The knockout of PARP-1 is sufficient to significantly impair DNA repair following damage via radiation (2) or cytotoxic (3) insult. The residual PARP-dependent repair activity (f10%) is due to PARP-2 (4, 5). These data imply that inhibition of only PARP-1 and PARP-2 will impair DNA repair following damage and that inhibition of other PARP family members is not required in the process. The functions of other PARP family members remain to be elucidated, but poly(ADP-ribosyl)ation has been implicated in many cellular processes, including differentiation, gene regulation, protein degradation, spindle maintenance, as well as replication and transcription (6).Higher expression of PARP in cancer compared with normal cells has been linked to...

ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and plateletderived growth factor (PDGF) receptor families (e.g., KDR IC 50 = 4 nmol/L) but has much less activity (IC 50 s > 1 Mmol/L) against unrelated RTKs, soluble tyrosine kinases, or serine/threonine kinases. The inhibition profile of ABT-869 is evident in cellular assays of RTK phosphorylation (IC 50 = 2, 4, and 7 nmol/L for PDGFR-B, KDR, and CSF-1R, respectively) and VEGF-stimulated proliferation (IC 50 = 0.2 nmol/L for human endothelial cells). ABT-869 is not a general antiproliferative agent because, in most cancer cells, >1,000-fold higher concentrations of ABT-869 are required for inhibition of proliferation. However, ABT-869 exhibits potent antiproliferative and apoptotic effects on cancer cells whose proliferation is dependent on mutant kinases, such as FLT3. In vivo ABT-869 is effective orally in the mechanism-based murine models of VEGF-induced uterine edema (ED 50 = 0.5 mg/kg) and corneal angiogenesis (>50% inhibition, 15 mg/kg). In tumor growth studies, ABT-869 exhibits efficacy in human fibrosarcoma and breast, colon, and small cell lung carcinoma xenograft models (ED 50 = 1.5 -5 mg/kg, twice daily) and is also effective (>50% inhibition) in orthotopic breast and glioma models. Reduction in tumor size and tumor regression was observed in epidermoid carcinoma and leukemia xenograft models, respectively. In combination, ABT-869 produced at least additive effects when given with cytotoxic therapies. Based on pharmacokinetic analysis from tumor growth studies, efficacy correlated more strongly with time over a threshold value (cellular KDR IC 50 corrected for plasma protein binding = 0.08 Mg/mL, z7 hours) than with plasma area under the curve or C max . These results support clinical assessment of ABT-869 as a therapeutic agent for cancer. [Mol Cancer Ther 2006;5(4):995 -1006]

A technique is described for performing frequency-selective signal suppression with a high degree of tolerance to RF field inhomogeneity. The method is called B 1 -insensitive train to obliterate signal (BISTRO). BISTRO consists of multiple amplitude-and frequency-modulated (FM) pulses interleaved with spoiler gradients. BISTRO was developed for the purpose of accomplishing bandselective signal removal, as in water suppression and outer-volume suppression (OVS), in applications requiring the use of an inhomogeneous RF transmitter, such as a surface coil. In the present work, Bloch simulations were used to illustrate the principles and theoretical performance of BISTRO. Its performance for OVS was evaluated experimentally using MRI and spectroscopic imaging of phantoms and in vivo animal and human brain. By using FM pulses featuring offset-independent adiabaticity, BISTRO permitted high-quality, broadband suppression with one (or two) discrete borders demarcating the edge ( Key words: adiabatic pulse; pulse sequence; volume localization; outer-volume suppression; frequency modulation A technique to accomplish band-selective signal suppression is a common need in many types of NMR experiments. Examples of such application include chemicalshift selective suppression of water or fat resonances and outer-volume suppression (OVS) in localized spectroscopy and imaging. In the most common approach, signal suppression is achieved by exploiting one or more frequency-selective pulses that convert the initial magnetization M 0 into transverse magnetization M xy that is subsequently dephased by pulsed B 0 gradients (1-11). In OVS techniques, M xy is dephased after being excited in slabs at selected locations and orientations. RF pulses used to excite the unwanted magnetization are commonly the amplitude-modulated (AM) variety. Such OVS approaches generally provide excellent signal suppression, provided the RF field is relatively homogeneous so that each position in the sample experiences a flip angle of 90°. When the flip angle deviates from 90°, some longitudinal magnetization M z remains, giving incomplete signal suppression. The projection presaturation (PP) method of and related techniques (7,8) solve this problem to a certain degree by employing a series of identical, small flip-angle pulses. For example, by repeating the small flip 32 times, the PP technique can offer high-quality suppression (M z / M 0 Ͻ 0.01) on resonance despite an approximately fivefold variation of RF amplitude. Although this degree of compensation for RF inhomogeneity is more than sufficient for experiments performed with volume coils, it is inadequate for RF transmission with a surface coil, which typically subjects the sample to a Ͼ10-fold variation in RF amplitude. Furthermore, because the frequency response profile produced by AM pulses is highly dependent on flip angle, RF transmission with a surface coil can lead to out-of-slice signal excitation, and hence to an undesirable reduction of M 0 in the tissue region(s) to be detected.To overco...

Aims: Pim-1 is a serine/threonine kinase that has been shown to play an integral role in the development of a number of human cancers, such as haematolymphoid malignancies. Recently, evidence has shown Pim-1 to be important in prostatic carcinogenesis. In order to further our understanding of its role in prostate cancer, we investigated Pim-1 expression in normal, premalignant, and malignant prostate tissue. Methods: Using immunohistochemistry, Pim-1 expression was analysed in prostate tissue from 120 radical prostatectomy specimens. In each case, Pim-1 staining was evaluated in benign prostatic epithelium, high grade prostatic intraepithelial neoplasia (PIN), and prostatic adenocarcinoma. The number of positively staining cells was estimated, and the intensity of staining was scored on a scale of 0 to 3+. Results: Pim-1 immunoreactivity was identified in 120 cases (100%) of adenocarcinoma, 120 cases (100%) of high grade PIN, and 62 cases (52%) of benign glands. The number of cells staining in benign epithelium (mean 34%) was much lower than that in high grade PIN (mean 80%; p,0.0001) or adenocarcinoma (mean, 84%; p,0.0001). There was no significant difference between high grade PIN and adenocarcinoma in the percentage of cells staining positively for Pim-1 (p = 0.34). The staining intensity for Pim-1 was significantly lower in benign prostatic epithelium than in PIN and adenocarcinoma (p,0.001). There was no statistically significant correlation between the level of Pim-1 expression and Gleason score, patient age, tumour stage, lymph node metastasis, perineural invasion, vascular invasion, surgical margin status, extraprostatic extension, or seminal vesicle invasion. Conclusions: Pim-1 expression is elevated in PIN and prostatic adenocarcinoma compared with benign prostatic epithelium. This finding suggests that upregulation of Pim-1 may play a role in prostatic neoplasia.