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Featuring PRECLINICAL AND CLINICAL CANCER THERAPEUTICS
VOLUME 17, NUMBER 3
Oncology Research, Vol. 17, pp. 93-101
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Investigation of Pericytes, Hypoxia, and Vascularity in Bladder Tumors: Association With Clinical Outcomes
Martina B. O'Keeffe,1 Andrea H. Devlin,2 Alan J. Burns,3 Tom A. Gardiner,4 Ian D. Logan,5 David G. Hirst,6 and Stephanie R. McKeown2
1Department of Life Sciences, University
of Limerick, Limerick, Ireland
2Biomedical Sciences Research Institute, University of Ulster, Coleraine, UK
3Neural Development Unit, Institute of Child Health, University College London, London, UK
4Centre for Ophthalmology and Vision Science, Queen's University Belfast, Belfast, UK
5School of Health Sciences, University of Ulster, Jordanstown, UK
6School of Pharmacy, Queen's University Belfast, Belfast, UK
The contribution of endothelial cell growth to angiogenesis has been widely studied; however, the involvement of pericytes is less well documented, especially in human tumors. In this study we aimed to quantify and assess the prognostic significance of pericyte coverage, the extent of hypoxia, and microvessel density (MVD) in normal bladder mucosa and urothelial carcinoma. Antibody to a-smooth muscle actin was used to assess the distribution of pericytes (mural/smooth muscle cells) in the microvessels of normal human bladder (n = 4) mucosa and in urothelial carcinoma (n = 47) samples; this was quantitated using microvessel pericyte index (MPI). The MVD was measured using two different methods (n = 47) and hypoxia was assessed using glucose transporter-1 (Glut-1) staining (n = 30). There was a 70% reduction in MPI in urothelial carcinomas compared to normal bladder mucosa (p < 0.0012); MPI did not correlate with tumor stage or grade. Ta and T1 superficial tumors were divided into two groups with a MPI of <15% or >15%. Progression-free survival was significantly shorter for tumors with MPI>15% (p = 0.0036). MVD had no prognostic value using either evaluation method. Glut-1 immunoreactivity was not prognostic in superficial urothelial carcinoma samples. Tumors with a higher MPI showed a greater Glut-1 immunoreactivity (p = 0.0051). Microvessels in urothelial carcinoma have a considerable loss of pericyte coverage compared to normal bladder mucosa. The data from this preliminary study indicate that progression-free survival was shorter in patients whose superficial tumors had higher pericyte coverage of the microvessels. This may be due to increased levels of hypoxia, as demonstrated by a significant increase in Glut-1 staining.
Key words: Angiogenesis; Bladder tumor; Glut-1; Hypoxia; Microvessel density; Pericyte; Urothelial carcinoma
Address correspondence to Prof. Stephanie R, McKeown, Biomedical Sciences Research Institute, University of Ulster, Cromore Road, Coleraine, Co. Londonderry, Northern Ireland, BT52 1SA. Tel: 02870 323542; Fax: 02870 324375; E-mail: firstname.lastname@example.org
Antiproliferative and Apoptotic Effects of Two New Pd(II) Methylsarcosinedithiocarbamate Derivatives on Human Acute Myeloid Leukemia Cells In Vitro
Donatella Aldinucci,1 Lara Cattaruzza,1 Debora Lorenzon,2 Lorena Giovagnini,3 Dolores Fregona,3 and Alfonso Colombatti1
1Experimental Oncology 2, Centro di
Riferimento Oncologico, IRCCS, Aviano (PN), Italy
2Clinical and Experimental Haematology Research Unit, Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy
3Department of Chemical Sciences, University of Padua, Padua, Italy
[Pd(MSDT)Cl]n palladium, chloro[methyl N-(dithiocarboxy-kS,kS´)-N-methylglycinate], and [Pd(MSDT) Br]n palladium, bromo[methyl N-(dithiocarboxy-kS,kS´)-N-methylglycinate], palladium (Pd)(II) derivatives are two newly synthesized Pd(II) derivatives of methylsarcosinedithiocarbamate (MSDT), containing a sulfur chelating ligand that is able to strongly bind the metal center, so preventing interactions with sulfur-containing enzymes. In fact, these reactions are believed to be responsible for the nephrotoxicity induced by platinum (II)-based drugs. Their activity has been evaluated in a panel of acute myeloid leukemia (AML) cell lines representing different French-American-British (FAB) subtypes and in the Philadelphia (Ph)-positive cell line K-562 and compared to cisplatin. Both compounds suppressed, in a dose-dependent manner, colony formation in methylcellulose with ID50 values comparable to those of the reference drug cisplatin, excluding the ML-3 cell line (ID50 10-fold lower than cisplatin). Exposure of HL-60, ML-3, NB-4, and THP-1 cell lines to a cytotoxic concentration of [Pd(MSDT)Br]n (5 mM) determined: downregulation of the antiapoptotic molecule Bcl-2, upregulation of the proapoptotic molecule Bax; apoptosis induction, as evaluated by APO2.7 and annexin V staining; mitochondrial membrane permeabilization; and DNA fragmentation. In ML-3 cells the Pd(II) complexes were more active than cisplatin in apoptosis induction. Finally, [Pd(MSDT)Br]n showed an inhibitory effect on clonogenic growth of hematopoietic progenitors (CFU-GM, CFU-GEMM, and BFUE) with both ID50 and ID90 comparable to those of cisplatin. Remarkably, the Pd(II) complex was more potent in inhibiting the clonogenic growth of the less differentiated AML cell lines KG-1a, HL-60, NB-4, ML-3, and THP-1 (ID50 ranging from 0.02 ± 0.001 to 0.52 ± 0.04 mM), compared to normal hematopoietic progenitors (ID50 of 2.1 ± 0.1, 3.8 ± 0.4, and 2.5 ± 0.2 mM) for CFU-GEMM, BFU-E, and CFU-GM, respectively). These data suggest that leukemic cells of myelomonoblast lineage might represent a preferential target for its cytotoxic activity compared to normal committed hemopoietic progenitor cells. Altogether, our results indicate that these new Pd(II) dithiocarbamate derivatives might represent novel potentially active drugs for the management of some selected myeloid leukemia strains, able to conjugate cytostatic and apoptotic activity with reduced toxicity.
Key words: Medicinal inorganic chemistry; Palladium compounds; Antineoplastic agents; Acute myeloid leukemia; Therapeutic index
Address correspondence to Donatella Aldinucci, Ph.D., Experimental Oncology 2, Centro di Riferimento Oncologico, IRCCS, via Franco Gallini 2, Aviano I-33081, Italy. Tel: 39-0434-659413; Fax: 39-0434-659428; E-mail: email@example.com
Aurora-A Transcriptional Silencing and Vincristine Treatment Show a Synergistic Effect in Human Tumor Cells
Laura Lentini,1 Angela Amato,1 Tiziana Schillaci,1 Lavinia Insalaco,1 and Aldo Di Leonardo1,2
1Dipartimento di Biologia Cellulare
e dello Sviluppo "A. Monroy", Università di Palermo, Viale delle
Scienze, Palermo, Italy
2C.O.B.S., Palermo, Italy
Aurora-A is a centrosome-associated serine/threonine kinase that is overexpressed in multiple types of human tumors. Primarily, Aurora-A functions in centrosome maturation and mitotic spindle assembly. Overexpression of Aurora-A induces centrosome amplification and G2/M cell cycle progression. Recently, it was observed that overexpression of Aurora-A renders cells resistant to cisplatin (CDDP)-, etoposide-, and paclitaxel-induced apoptosis.Our results indicate that already in initial stages of cancer progression Aurora-A overexpression could have a major role in inducing supernumerary centrosomes and aneuploidy, as shown by immunohistochemistry on tissue sections from various stages of human colon cancer. Aneuploidy was also observed after Aurora-A ectopic overexpression in colon cancer cells with MIN phenotype. Silencing of Aurora-A by RNA interference in tumor cell lines triggered arrest of the cell cycle associated to apoptosis/mitotic catastrophe. Finally, Aurora-A transcriptional silencing seems to confer cancer cells a greater sensitivity to chemotherapy by vincristine, indicating Aurora-A as a possible gene target in cancer therapy.
Key words: Aurora A/STK15; Centrosome amplification; Aneuploidy; CIN
Address correspondence to Aldo Di Leonardo, Dipartimento di Biologia Cellulare e dello Sviluppo "A. Monroy", Università di Palermo, Viale delle Scienze, Parco d'Orleans, Palermo, Italy. Tel: +39 091 6577340; Fax: +39 091 6577347; E-mail: firstname.lastname@example.org
Association of Polymorphisms in Base Excision Repair Genes With the Risk of Breast Cancer: A Case-Control Study in North Indian Women
Amit Kumar Mitra,1 Neetu Singh,1 Ashok Singh,1 Vivek Kumar Garg,2 Amit Agarwal,3 Mandira Sharma,2 Rashmi Chaturvedi,2 and Srikanta Kumar Rath1
1Genotoxicity Laboratory, Toxicology
Division, Central Drug Research Institute, Lucknow, Uttar Pradesh, India
2Lucknow Cancer Institute, Lucknow, Uttar Pradesh, India
3Department of Endocrine Surgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
Inheritance of common genetic variants at one or more base excision repair (BER) genes may result in a reduced DNA repair capacity and in an increased risk of cancers like breast cancer. The present case-control study with 390 north Indian women (155 breast cancer cases and 235 controls) was aimed to investigate the association of seven nonsynonymous BER gene polymorphisms viz. rs1130409/T1865G (APEX1), rs1799782/T22142C (XRCC1), rs25487/G23990A (XRCC1), rs4989588/T3337A (FEN1), rs4989586/G3259A (FEN1), rs4989587/C3315T (FEN1), and rs1050525/G6941T (PCNA) with breast cancer susceptibility. Statistically significant association with breast cancer risk was observed for rs1130409 homozygous mutant GG [odds ratio (OR) 3.35, 95% confidence interval (CI) 1.36-8.26), heterozygous GT (OR 2.42, 95% CI 1.56-3.76), and combined mutant (GT + GG) (OR 2.52, 95% CI 1.65-3.86] genotypes and rs25487 homozygous mutant AA (OR 2.91, 95% CI 1.66-5.10) and combined mutant (AA + AG) (OR 1.41, 95% CI 0.903-2.19) genotypes, whereas protective association was exhibited by rs1799782 homozygous mutant CC (OR 0.413, 95% CI 0.082-2.08), heterozygous TC (OR 0.351, 95% CI 0.189-0.650), and combined mutant (TC + CC) (OR 0.357, 95% CI 0.199-0.641) genotypes. Association study using reconstructed haplotypes of XRCC1 gene showed positive association for the TA haplotype (OR 2.014, 95% CI 1.462-2.775) and a protective association for the CG haplotype (OR 0.173, 95% CI 0.052-0.576) pertaining to breast cancer risk. The results indicate that the polymorphisms rs1130409 (APEX1) and rs25487 (XRCC1) might be involved in contributing towards breast cancer susceptibility, while rs1799782 (XRCC1) might have protective influence.
Key words: Base excision repair (BER); North Indian women; Single nucleotide polymorphism (SNP); Odds ratio; Relative risk; Confidence interval
Address correspondence to Srikanta Kumar Rath, Scientist, Genotoxicity Laboratory, Division of Toxicology, Central Drug Research Institute, Lucknow, 226001, Uttar Pradesh, India. Tel: 91-0522-22612411-4316; Fax: 91-0522-2623405; E-mail: email@example.com
Long-Term Results of Dose-Intensive Chemotherapy With G-CSF Support (TCC-NHL-91) for Advanced Intermediate-Grade Non-Hodgkin's Lymphoma: A Review of 59 Consecutive Cases Treated at a Single Institute
Miyuki Akutsu,1 Saburo Tsunoda,1 Tohru Izumi,1 Masaru Tanaka,1 Susumu Katano,2 Koichi Inoue,1 Seiji Igarashi,3 Kaoru Hirabayashi,3 Yusuke Furukawa,4 Ken Ohmine,1,4 Kazuya Sato,1,4 Hiroyuki Kobayashi,1,4 Keiya Ozawa,4 Keita Kirito,1,5 Takahiro Nagashima,1,5 Satoshi Teramukai,6 Masanori Fukushima,6 and Yasuhiko Kano1
1Division of Hematology, Tochigi Cancer
Center, Tochigi, 320-0834, Japan
2Division of Radiation Oncology, Tochigi Cancer Center, Tochigi, 320-0834, Japan
3Division of Pathology, Tochigi Cancer Center, Tochigi, 320-0834, Japan
4Division of Hematology, Jichi Medical University, Tochigi 329-0498, Japan
5Division of Hematology, Yamanashi University, Yamanashi 409-3898, Japan
6Division of Clinical Trial Design and Management, Translational Research Center, Kyoto University Hospital, Kyoto, 606-8507, Japan
We evaluated the long-term outcome of very dose-intensive chemotherapy (TCC-NHL-91) for advanced intermediate-grade lymphoma, in which an eight-cycle regimen with 11 drugs was given with granulocyte colony-stimulating factor (G-CSF) support (total 18 weeks). Fifty-nine patients were treated during February 1, 1991 and March 31, 2001 (median age: 48 years). Forty-three patients (73%) were in a high-intermediate risk or high-risk group (HI/H) according to the age-adjusted International Prognostic Index (aa-IPI). Forty-six patients received 7 or 8 cycles of therapy. Ten of 15 patients over age 60 stopped before 7 cycles. Forty-three patients with an initial bulky mass or a residual mass received involved-field radiation. Overall, 56 patients (95%) achieved complete remission (CR). Grade 4 hematotoxicity was observed in all patients. With a median follow-up of 128 months, the 10-year overall survival (OS) and progression-free survival (PFS) rates were 76% and 61%, respectively. Neither aa-IPI risk factors nor the index itself was associated with response, OS, or PFS. One patient died of sepsis during the therapy and one died of secondary leukemia. This retrospective study suggests that the TCC-NHL-91 regimen achieves high CR, OS, and PFS in patients with advanced intermediate-grade lymphoma up to 60 years old and may be a valuable asset in the management of this disease. Further evaluation and prospective studies of the TCC-NHL-91 are warranted.
Key words: TCC-NHL-91; G-CSF; Aggressive lymphoma; CNS lymphoma
Address correspondence to Yasuhiko Kano, Divison of Hematology, Tochigi Cancer Center, Yonan 4-9-13, Utsunomiya, Tochigi, 320-0834, Japan. Tel: 011-81-28-658-5151; Fax: 011-81-28-658-5488; E-mail: firstname.lastname@example.org