Sustained in vivo regression of Dunning H rat prostate cancers treated with combinations of androgen ablation and Trk tyrosine kinase inhibitors, CEP-751 (KT-6587) or CEP-701 (KT-5555).

The indolocarbazole analogue CEP-751 is a potent and selective tyrosine kinase inhibitor of the neurotrophin-specific trk receptors that has demonstrated antitumor activity in nine different models of prostate cancer growth in vivo. In the slow-growing, androgen-sensitive Dunning H prostate cancers, which express trk receptors, CEP-751 induced transient regressions independent of effects on cell cycle. Because androgen ablation is the most commonly used treatment for prostate cancer, we examined whether the combination treatment of CEP-751 with castration would lead to better antitumor efficacy than either treatment alone. For a 60-day period, H tumor-bearing rats received treatment with either castration, CEP-751 (10 mg/kg once a day s.c. for 5 days every 2 weeks), a combination of both, or vehicle. Castration caused tumor regression, followed by tumor regrowth in 4-6 weeks, whereas intermittent CEP-751 treatments resulted in tumor regressions during each treatment, which were followed by a period of regrowth between intermittent drug treatment cycles. Overall, both monotherapies significantly inhibited tumor growth compared with the vehicle-treated control group. However, the combination of castration and concomitant CEP-751 produced the most dramatic results: sigificantly greater tumor regression than either therapy alone, with no signs of regrowth. A related experiment using an orally administered CEP-751 analogue (CEP-701), as the trk inhibitor, and a gonadotrophin-releasing hormone agonist, Leuprolide, to induce androgen ablation demonstrated similar results, indicating that these effects could be generalized to other forms of androgen ablation and other trk inhibitors within this class. In addition, when CEP-701 was given sequentially to rats bearing H tumors, which were progressing in the presence of continuous androgen ablation induced by Leuprolide, regression of the androgen-independent tumors occurred. In summary, these data demonstrate that CEP-751 or CEP-701, when combined with surgically or chemically induced androgen ablation, offer better antitumor efficacy than either monotherapy and suggest that each therapy produces prostate cancer cell death through complementary mechanisms.     

In vivo circumvention of human colon carcinoma resistance to bleomycin.

Metabolic inactivation of bleomycin (BLM) by cysteine proteinase-like enzymes is thought to be a major mechanism of BLM tumor resistance. We now report that the human colon carcinoma COLO-205 is highly resistant to BLM and that E-64, a cysteine proteinase inhibitor, sensitizes COLO-205 to BLM. Treatment of COLO-205-bearing nude mice with either E-64 (40 mg/kg) or BLM (10 mg/kg) alone did not inhibit COLO-205 growth. However, pretreatment with E-64 prior to BLM prevented these xenografts from growing. Analysis by high performance liquid chromatography of in vivo BLM metabolism following [3H]BLM A2 treatment of COLO-205-bearing nude mice showed a different metabolic profile among the various organs and the tumor. Whereas [3H]BLM A2 was the only major radioactive peak detected in sera and tumors, several metabolites, including deamido-BLM A2, were found in kidney, liver, and lung as early as 15 min. Pretreatment of mice with E-64 inhibited tumor, kidney, and lung BLM A2 metabolism. Furthermore, pretreatment with E-64 increased BLM A2 accumulation in tumors (6.1-fold), kidney (4.0-fold), lung (2.8-fold), liver (1.8-fold), and serum (1.7-fold). E-64 pretreatment did not enhance the major toxicity of BLM, pulmonary fibrosis, as determined by both lung hydroxyproline levels and histopathology. Thus, the cysteine proteinase inhibitor E-64 affects the metabolic fate and the levels of accumulation of BLM in vivo. These results demonstrate that resistance of human COLO-205 tumors to BLM can be circumvented by E-64 without enhancement of the major side effect of BLM, suggesting a possible clinical use of this combination therapy.     

Mersacidin, a new antibiotic from Bacillus. In vitro and in vivo antibacterial activity.

Mersacidin is a new peptide antibiotic of the proposed lantibiotic family. It is active in vitro and in vivo against Gram-positive bacteria including the methicillin-resistant Staphylococci. Its in vitro activity is less than those of vancomycin and erythromycin but it shows much higher activity in the in vivo system than can be expected from the in vitro testing results. A water soluble potassium salt has been prepared which has an activity profile similar to that of mersacidin, but has better in vivo activity against Streptococcus pyogenes than the parent compound.     

Cytogenetic study of maturing granulocytes in bone marrow of patients with acute myelogenous leukemia.

To determine the cytogenetic origin of maturing granulocytes in the bone marrow of patients with acute myelogenous leukemia, bone marrow cells were studied using a modified cytogenetic technique, which does not disrupt the cell membrane, in conjunction with periodic acid-Schiff (PAS) staining. In four cases successfully studied, myeloblasts were PAS-negative and granulocytes were PAS-positive. In three cases successfully studied following 0-2 days of culture, metaphase spreads with abnormal karyotypes characteristic of the patients' leukemic clones were seen in five of five, six of nine, and four of four PAS-positive cells successfully studied. These patients' bone marrows were AN, AA, and AA, respectively, by standard cytogenetic study. Therefore, the cytogenetic status of PAS-positive cells did not necessarily correlate with presence or absence of normal metaphases determined by standard cytogenetic study. Bone marrow cells which underwent full and partial granulocytic maturation in suspension culture were studied following 2 weeks of culture. Abnormal karyotypes were seen in five of five and two of two metaphases in PAS-positive cells successfully studied in two patients. Therefore, we have demonstrated that when acute myelogenous leukemia cells undergo myeloid maturation in culture, the mature cells may be definitely proven to derive from leukemic progenitors rather than from normal stem cells.     

Phenotype in girls and women with Turner syndrome: Association between dysmorphic features,karyotype and cardio-aortic malformations

Introduction

Turner syndrome (TS) is a genetic disorder characterized by the (partial) absence or a structural aberration of the second sex chromosome and is associated with a variety of phenotypes with specific physical features and cardio-aortic malformations. The objective of this study was to gain a better insight into the differences in dysmorphic features between girls and women with TS and to explore the association between these features, karyotype and cardio-aortic malformations.

Design, synthesis and antimycobacterial activity of some novel imidazo[1,2-c]pyrimidines

Tuberculosis, due to its relentless nature, is now a major public health threat. The concomitant resurgence of TB with the MDR- or XDR-TB and HIV/AIDS pandemic has exposed the frailties of the current drug armatorium. Based on isosteric replacement and good 3D structural similarity between PA-824, a novel antimycobacterial agent undergoing clinical trials, and imidazo[1,2-c]pyrimidines, we have designed novel imidazo[1,2-c]pyrimidines. The designed molecules were synthesized by nucleophilic displacement of chloro group of various substituted 4-chloropyrimidines by ethanolamine followed by cyclisation of these 4-(2-hydroxyethyl)aminopyrimidines to imidazo[1,2-c]pyrimidines in good yield. All the compounds were screened for their antimycobacterial activity on Mycobacterium tuberculosis H37Rv strain by 1% proportion method. Some of the synthesized compounds exhibited potent antimycobacterial activity with MIC values in the range of 2–20 μg/mL.     

Incidence of gliomas by anatomic location

The anatomic location of a glioma influences prognosis and treatment options. The aim of our study was to describe the distribution of gliomas in different anatomic areas of the brain. A representative population-based sample of 331 adults with glioma was used for preliminary analyses. The anatomic locations for 89 patients from a single center were analyzed in more detail from radiologic imaging and recorded on a three-dimensional 1 x 1 x 1-cm grid. The age-standardized incidence rate of gliomas was 4.7 per 100,000 person-years. The most frequent subtypes were glioblastoma (47%) and grade II-III astrocytoma (23%), followed by oligodendroglioma and mixed glioma. The gliomas were located in the frontal lobe in 40% of the cases, temporal in 29%, parietal in 14%, and occipital lobe in 3%, with 14% in the deeper structures. The difference in distribution between lobes remained after adjustment for their tissue volume: the tumor:volume ratio was 4.5 for frontal, 4.8 for temporal, and 2.3 for parietal relative to the occipital lobe. The area with the densest occurrence was the anterior subcortical brain. Statistically significant spatial clustering was found in the three-dimensional analysis. No differences in location were found among glioblastoma, diffuse astrocytoma, and oligodendroglioma. Our results demonstrate considerable heterogeneity in the anatomic distribution of gliomas within the brain.