ognizant Communication Corporation



Oncology Research, Vol. 16, pp. 351-359
0965-0407/07 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2007 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

TAT Peptide-Modified Liposomes Provide Enhanced Gene Delivery to Intracranial Human Brain Tumor Xenografts in Nude Mice

Bhawna Gupta, Tatiana S. Levchenko, and Vladimir P. Torchilin

Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA

In this study, we have investigated the potential of trans-activating transcriptional activator peptide (TATp)-modified liposomes to enhance the delivery of the model gene, plasmid encoding for the green fluorescent protein (pEGFP-N1), to human brain tumor U-87 MG cells in vitro and in an intracranial model in nude mice. The TATp-lipoplexes were characterized at lipid/DNA (+/-) charge ratios of 0.2, 5, 10, and 20 for size analysis and DNA complexation. The size distribution of DNA-loaded TATp-liposomes was narrow and the DNA complexation was firm at lipid/DNA (+/-) charge ratios of 5 and higher. TATp-lipoplexes had demonstrated an enhanced delivery of pEGFP-N1 to U-87 MG tumor cells in vitro at lipid/DNA (+/-) charge ratios of 5 and 10. In vivo transfection of intracranial brain tumors by intratumoral injections of TATp-lipoplexes showed an enhanced delivery of pEGFP-N1 selectively to tumor cells and subsequent effective transfection compared to plain plasmid-loaded lipoplexes. No transfection (green fluorescence of the GFP) was noted in the normal brain adjacent to tumor.

Key words: Brain tumor; Intracranial; U-87 MG astrocytoma; Gene delivery; Liposome; TAT peptide

Address correspondence to Vladimir P. Torchilin, Northeastern University, Department of Pharmaceutical Sciences, 312 Mugar Building, 360 Huntington Avenue, Boston, MA 02115, USA. Tel: 617-373-3206; Fax: 617-373-8886; E-mail: v.torchilin@neu.edu

Oncology Research, Vol. 16, pp. 361-374
0965-0407/07 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2007 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Increased Preclinical Efficacy of Irinotecan and Floxuridine Coencapsulated Inside Liposomes Is Associated With Tumor Delivery of Synergistic Drug Ratios

Troy O. Harasym,1 Paul G. Tardi,1 Natashia L. Harasym,1 Pierrot Harvie,1 Sharon A. Johnstone,1 and Lawrence D. Mayer1,2

1Celator Pharmaceuticals Corp., Vancouver BC, V6P 6P2 Canada
2Celator Pharmaceuticals Inc., Princeton, NJ 08540, USA

Whether anticancer drug combinations act synergistically or antagonistically often depends on the ratio of the agents being combined. We show here that combinations of irinotecan and floxuridine exhibit drug ratio-dependent cytotoxicity in a broad panel of tumor cell lines in vitro where a 1:1 molar ratio consistently provided synergy and avoided antagonism. In vivo delivery of irinotecan and floxuridine coencapsulated inside liposomes at the synergistic 1:1 molar ratio (referred to as CPX-1) lead to greatly enhanced efficacy compared to the two drugs administered as a saline-based cocktail in a number of human xenograft and murine tumor models. When compared to liposomal irinotecan or liposomal floxuridine, the therapeutic activity of CPX-1 in vivo was not only superior to the individual liposomal agents, but the extent of tumor growth inhibition was greater than that predicted for combining the activities of the individual agents. In contrast, liposome delivery of irinotecan:floxuridine ratios shown to be antagonistic in vitro provided antitumor activity that was actually less than that achieved with liposomal irinotecan alone, indicative of in vivo antagonism. Synergistic antitumor activity observed for CPX-1 was associated with maintenance of the 1:1 irinotecan:floxuridine molar ratio in plasma and tumor tissue over 16-24 h. In contrast, injection of the drugs combined in saline resulted in irinotecan:floxuridine ratios that changed 10-fold within 1 h in plasma and sevenfold within 4 h in tumor tissue. These results indicate that substantial improvements in the efficacy of drug combinations may be achieved by maintaining in vitro-identified synergistic drug ratios after systemic administration using drug delivery vehicles.

Key words: Combination chemotherapy; Synergy; Colorectal cancer; Liposome delivery; Irinotecan; Floxuridine

Address correspondence to Dr. Lawrence Mayer, Celator Pharmaceuticals, Corp., 1779 West 75th Ave., Vancouver, BC V6P 6P2 Canada. Tel: 604-675-2103; Fax: 604-708-5883; E-mail: lmayer@celatorpharma.com

Oncology Research, Vol. 16, pp. 375-381
0965-0407/07 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2007 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

IL-2, TNF-a, and Leptin: Local Versus Systemic Concentrations in NSCLC Patients

Giovanna E. Carpagnano,1 Antonio Spanevello,2 Claudia Curci,1 Francesco Salerno,2 Grazia P. Palladino,1 Onofrio Resta,3 Giuseppe Di Gioia,3 Francesco Carpagnano,4 and Maria P. Foschino Barbaro1

1Institute of Respiratory Disease, Department of Medical and Occupational Sciences, University of Foggia, Italy
2Fondazione Salvatore Maugeri, Care and Research Institute, Cassano delle Murge, Bari, Italy
3Institute of Respiratory Disease, University of Bari, Bari, Italy
4Department of Thoracic Surgery, San Paolo Hospital, Bari, Italy

One recent line of cancer research shows increasing interest for biological factor such as IL-2, TNF-a, and leptin, which have been found to participate in the development and progression of non-small cell lung cancer (NSCLC). The aim of this study was to measure IL-2, TNF-a, and leptin concentrations in the airways and in the systemic circle of patients with NSCLC, investigating the role of these factors in the lung tumors. We enrolled 32 patients (17 men, 71 ± 7 years) with a histological diagnosis of NSCLC and 20 healthy ex-smoker controls, negative for computed tomography of the chest (14 men, 69 ± 8 years). IL-2, TNF-a, and leptin levels were measured in the serum, the urine, the bronchoalveolar lavage, the induced sputum, and exhaled breath condensate (EBC) of patients enrolled by means of a specific enzyme immunoassay kit. Higher concentrations of IL-2, TNF-a and leptin were found in NSCLC patients than in controls (p < 0.0001). A statistically significant increase of IL-2, TNF-a, and leptin concentrations was observed in patients from stage I to stage III of NSCLC. These findings suggest that IL-2, TNF-a, and the leptin play an important role in the cancerogenesis of NSCLC. Their measure in the EBC could be proposed as noninvasive markers for an early detection of NSCLC and in the follow-up of this tumor.

Key words: IL-2; TNF-a; Leptin; Non-small cell lung cancer (NSCLC); Exhaled breath condensate; Systemic circle

Address correspondence to Dr. Giovanna Elisiana Carpagnano, Institute of Respiratory Disease, Department of Medical and Occupational Sciences, University of Foggia, Foggia, Italy. Tel: 0039 0881 703040; Fax: 0039 0881 703040; E-mail: ge.carpagnano@unifg.it

Oncology Research, Vol. 16, pp. 383-387
0965-0407/07 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2007 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Prenatal and Perinatal Risk Factors and Testicular Cancer: A Hospital-Based Case-Control Study

Gabe S. Sonke,1 Shine Chang,2 Sara S. Strom,2 Anne M. Sweeney,2 J. Fred,3* and Alice J. Sigurdson3**

1Divisions of Cancer Epidemiology and Genetics and Cancer Prevention, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA
2Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
3Department of Epidemiology, The University of Texas School of Public Health, Houston, TX, USA

Some evidence exists to support the hypothesis that elevated levels of circulating maternal estrogens during early pregnancy may increase risk of testicular germ cell cancer. However, the results from studies evaluating maternal factors have been mixed. We evaluated maternal factors, particularly those associated with excess estrogen levels, as risk factors for testicular cancer. We conducted a hospital-based case-control study at The University of Texas M. D. Anderson Cancer Center in Houston, Texas of 144 testicular cancer patients diagnosed between 1990 and 1996 and 86 friend controls matched to cases on age, race, and state of residence. Risk factor data about the mother, the son, and the pregnancy were obtained from the mothers by telephone interviews and from the sons by self-administered questionnaires. Extreme nausea during the first trimester of pregnancy was associated with an elevated risk of testicular cancer [odds ratio (OR) = 2.0; 95% confidence interval (CI) = 1.0-3.9]. Adjustment for potential confounders slightly lowered this risk (OR = 1.8; 95% CI = 0.9-3.8). Risks were modestly increased for other factors that are proxy measures for maternal estrogens, including preterm delivery (OR = 2.2; 95% CI = 0.4-12.9), birth weight <3000 g (OR = 2.4; 95% CI = 0.7-8.1), and birth weight >4000 g (OR = 1.7; 95% CI = 0.9-3.2), albeit nonsignificantly so. Our finding that severe nausea was associated with increased testicular cancer risk adds evidence to support the in utero estrogen exposure hypothesis because nausea early in pregnancy is related to rising levels of circulating estrogens. For other factors, which are less direct measures of maternal estrogens, the modest associations found indicate a suggestive pattern in support of the excess estrogen hypothesis.

Key words: Testicular neoplasms; Estrogens; Risk factors; Maternal exposure; Case-control studies

Address correspondence to Gabe Sonke, M.D., Ph.D., at his current address: Department of Medical Oncology, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel: +31 20 512 9111; Fax: +31 20 512 2572; E-mail: g.sonke@nki.nl

* Dr. Annegers is deceased.
**Current address: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA.

Oncology Research, Vol. 16, pp. 389-394
0965-0407/07 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2007 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Radiation-Induced Antitumor Properties of Vitamin B5 (Pantothenic Acid) and its Effect on Mitomycin C Activity: Experiments In Vitro

Heike Schittl and Nikola Getoff

Section Radiation Biology, Department of Nutrition Sciences, The University of Vienna, A-1090 Vienna, Austria

Vitamin B5 (pantothenic acid) shows a strongly pronounced antitumor effect under the influence of ionizing radiation. In the frame of experiments in vitro (model: Escherichia coli bacteria, AB1157) performed under the exact knowledge of concentration and kind of the free radicals acting in the various aqueous media (pH 7.4) the following was established: (i) vitamin B5 possesses a very intense antitumor property, (ii) it exerts a strong synergistic effect on mitomycin C (MMC), (iii) the oxidizing species (OH., O2.-) appears to be most important in the initiation of the observed effect. The generated radiolytic products from vitamin B5 very likely also play an important role in this respect.

Key words: Vitamin B5; Pantothenic acid; Antitumor effect; Synergistic action of vitamin B5

Address correspondence to Prof. Dr. Nikola Getoff, Section Radiation Biology, Department of Nutrition Science, The University of Vienna, Althanstr. 14, UZA II, A-1090 Vienna, Austria. Tel: +43-(1)-4277-54966; Fax: +043-(1)-4277-54965; E-mail: nikola.getoff@univie.ac.at

Oncology Research, Vol. 16, pp. 395-403
0965-0407/07 $90.00 + .00
E-ISSN 1555-3906
Copyright © 2007 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Expression of MDR1 in Epithelial Ovarian Cancer and its Association With Disease Progression

Lingeng Lu,1 Dionyssios Katsaros,2 Andrew Wiley,1 Irene A. Rigault de la Longrais,2 Manuela Puopolo,2 and Herbert Yu1

1Department of Epidemiology and Public Health, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520-8034, USA
2Department of Obstetrics and Gynecology, Gynecologic Oncology and Breast Cancer Unit, University of Turin, Turin, Italy

The purposes of this study were to analyze <i>MDR1<i> expression in ovarian tumors prior to chemotherapy, to correlate the expression with p16, IGFs, ERa, and BRCA1, and to examine the association of MDR1 expression with ovarian cancer prognosis. A primary ovarian cancer cohort of 206 patients after surgery was followed up. MDR1, IGFs, ERa, p16, and BRCA1 expressions were analyzed in ovarian tumor samples using quantitative real-time PCR.MDR1 was detected in 177 of 206 specimens. MDR1 expression was positively correlated with IGFBP3, ERa, p16, and BRCA1, but not correlated with IGF-II, age, and other clinicopathological parameters. MDR1 expression significantly elevated the risk for disease progression (p = 0.02), and this association remained statistically significant after controlling for patient age and clinicopathological parameters or other correlated genes. No association was found between MDR1 expression and overall survival. MDR1 expression may be an independent marker for ovarian cancer progression and combination of different agents targeting different molecules may improve the outcome of ovarian cancer treatment and prevent drug resistance.

Key words: Ovarian cancer; MDR1; Prognosis

Address correspondence to Herbert Yu, Department of Epidemiology and Public Health, Yale Cancer Center, Yale University School of Medicine, 60 College Street, New Haven, CT 06520-8034, USA. Tel: 203-785-5688; Fax: 203-785-2850; E-mail: herbert.yu@yale.edu