|ognizant Communication Corporation|
AN INTERNATIONAL JOURNAL
INCORPORATING ANTI-CANCER DRUG DESIGN
VOLUME 16, NUMBER 7
Oncology Research, Vol. 16, pp. 299-312
0965-0407/07 $90.00 + .00
Copyright © 2007 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.
ECTO-NOX Target for the Anticancer Isoflavene Phenoxodiol
D. James Morré,1 P.-J. Chueh,2 Kader Yagiz,3 Andrew Balicki,1 Chinpal Kim,1 and Dorothy M. Morré3
1Department of Medicinal Chemistry and Molecular Pharmacology,
Purdue University, West Lafayette, IN 47907, USA
2Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40227 Taiwan, Republic of China
3Department of Foods and Nutrition, Purdue University, West Lafayette, IN 47907, USA
Phenoxodiol, a synthetic isoflavene with clinical efficacy in the management of ovarian and other forms of human cancer, blocked the activity of a cancer-specific and growth-related cell surface ECTO-NOX protein with both oxidative (hydroquinone) and protein disulfide-thiol interchange activity designated tNOX. Purified recombinant tNOX bound phenoxodiol with high affinity (Kd of 50 nM). The tNOX protein appeared to be both necessary and sufficient for the cancer-specific cytotoxicity of phenoxodiol. Growth inhibition of fibroblasts from embryos of mice expressing a tNOX transgene, but not from wild-type mice, was inhibited by phenoxodiol followed by apoptosis. Both the oxidative and protein disulfide-thiol interchange activities that alternate to generate the complex set of oscillations with a period length of 22 min (24 min for the constitutive counterpart CNOX) that characterize ECTO-NOX proteins respond to phenoxodiol. Oxidation of NADH or reduced coenzyme Q10 was rapidly blocked by phenoxodiol. In contrast, the protein disulfide-thiol interchange activity measured either by the restoration of activity to scrambled and inactive RNase or from the cleavage of dithiodipyridine (EC50 of 50 nM) was inhibited progressively over an interval of 60 min that spanned three cycles of activity. Inhibition of the latter paralleled the inhibition of cell enlargement and the consequent inability of inhibited cells to initiate traverse of the cell cycle. Activities of constitutive ECTO-NOX (CNOX) forms of either cancer or noncancer cells were unaffected by phenoxodiol to help explain how the cytotoxic effects of phenoxodiol may be restricted to cancer cells.
Key words: ECTO-NOX; NADH oxidase; tNOX; Cancer; Phenoxodiol; Isoflavene
Address correspondence to D. James Morré, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 201 S. University Street, West Lafayette, IN 47907-2064, USA. Tel: 765-494-1388; Fax: 765-494-4007; E-mail: firstname.lastname@example.org
Antitumor Effects of Hydroxycamptothecin-Loaded Poly[ethylene glycol]-poly[g-benzyl-L-glutamate] Micelles Against Oral Squamous Cell Carcinoma
Xue-Qiang Ding,1* Dan Chen,1* An-Xun Wang,1 Su Li,2 Yu Chen,1 and Ji Wang1
1Department of Oral & Maxillofacial Surgery, First Affiliated
Hospital, Sun Yat-Sen University, Guangzhou City, Guangdong Province, 510080,
2Skate Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou City, Guangdong Province, 510080, P.R. China
Therapeutic use of hydroxycamptothecin (HCPT), a promising antitumor agent, is limited by its poor solubility and rapid destruction. Amphiphilic block copolymer micelle carriers possess significant potential for improving drug solubility and stability. Poly[ethylene glycol]-poly[g-benzyl-L-glutamate] (PEG-PBLG) micelles were prepared and loaded with the active lactone form of HCPT using an uncomplicated dialysis method. HPLC and scanning electron microscopy studies revealed an encapsulation efficiency of 56.8% and a core-shell figure with a mean diameter of 200 nm. Encapsulated HCPT lactone was compared with the less active, open ring-carboxylated HCPT-Na+ soluble form generated in vivo from the free active lactone for activity against oral squamous cell carcinoma. Cytotoxicity in vitro was measured in cultured Tca8113 cells by the MTT assay and microscopy techniques. The golden hamster cheek pouch squamous cell carcinoma model was employed for in vivo studies; encapsulated lactone and open ring-carboxylated forms of HCPT were administered intraperitoneally, followed by determinations of tumor growth rate and inhibition ratio. PEG-PBLG micelles were not cytotoxic in vitro. At 48 h of treatment, open ring-carboxylated HCPT proved significantly more cytotoxic in vitro than encapsulated HCPT lactone. At 96 h, however, the open ring-carboxylated and encapsulated drugs displayed comparable in vitro cytotoxicities. In the in vivo squamous cell carcinoma model, encapsulated HCPT lactone produced greater and more prolonged tumor suppression compared to the open ring-carboxylated form. The antitumor effects of HCPT/PEG-PBLG micelles against oral squamous cell carcinoma in vivo are concluded to be superior to those exerted by open ring-carboxylated HCPT.
Key words: Amphiphilic block copolymer micelles; Poorly soluble drugs; Hydroxycamptothecin (HCPT); Poly[ethylene glycol] (PEG); Poly[g-benzyl-L-glutamate] (PBLG); Oral squamous cell carcinoma (OSCC)
Address correspondence to Dr. Xue-Qiang Ding, Department of Oral & Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou City, Guangdong Province, 510080, P.R. China. Tel: +86 20 87335059; Fax: +86 20 87333122; E-mail: email@example.com
*The first two authors contributed equally to this work.
DMBA/TPA-Induced Tumor Formation Is Aggravated in Human Papillomavirus Type 16 E6/E7 Transgenic Mouse Skin
Myoung Ok Kim,1* Sung Hyun Kim,1* Mi Jung Shin,1 Dong Hoon Yu,1 Bong Soo Kim,1 Kyu Tae Chang,2 Sanggyu Lee,1 Yong Bok Park,1 Tae-Hoon Lee,3 and Zae Young Ryoo1
1School of Life Sciences and Biotechnology, College of Natural
Sciences, Kyungpook National University, Daegu, 702-701, Korea
2Laboratory of Primate Research, Korea Research Institute of Bioscience & Biotechnology, Oun-dong, Yusong-ku, Daejon 305-333, Korea
3Department of Oral Biochemistry, School of Dentistry, Chonnam National University, 300 Yongbong-Dong, Buk-ku, Gwangju 500-757, Korea
Human papillomavirus type 16 (HPV16) is a major causative factor in the development of uterine cervical carcinomas. We investigated the role of E6/E7 in tumor formation. Skin-specific E6/E7 transgenic mice showed approximately twice as many tumors compared with nontransgenic mice in dimethylbenz[a]anthracene (DMBA)-initiated and a 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted two-stage skin carcinogenesis. This model showed a significant increase of epidermal cell proliferation in the transgenic mice. The 8-hydroxy-2´deoxyguanosine (8OH-dG) detection assay showed that oxidative DNA damage was significantly higher in the transgenic mice after TPA treatments. The overexpression of E6/E7 in the skin in the DMBA/TPA two-stage-induced carcinogenesis model aggravated the incidence of tumor formation. HPV16 E6/E7 appears to act as an enhancer of carcinogenesis that requires initiation by DMBA and promotion by TPA.
Key words: HPV16 E6/E7; Transgenic mice; hK14 promoter; Skin cancer; Keratinocytes; DMBA/TPA
Address correspondence to Zae Young Ryoo, Ph.D., School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, 1370 Sankyuk-dong, Buk-ku, Daegu 702-701, Korea. Tel: 82-53-950-7361; Fax: 82-53-943-6925; E-mail: firstname.lastname@example.org
*These authors contributed equally to this work.
Relationship Between the Loss of Heterozygosity and Tobacco Smoking in Pulmonary Adenocarcinoma
Tomofumi Yohena,1,3 Ichiro Yoshino,1 Tomoyoshi Takenaka,1 Taro Ohba,1 Hidenori Kouso,1 Atsushi Osoegawa,1 Motoharu Hamatake,1 Shinya Oda,2 Yukio Kuniyoshi,3 and Yoshihiko Maehara1
1Department of Surgery and Science, Graduate School of Medical
Sciences, Kyushu University, Fukuoka 812-8582, Japan
2Cancer Genetics Laboratory, Institute for Clinical Research, National Kyushu Cancer Center, Fukuoka 811-1395, Japan
3Department of Bioregulatory Medicine, Thoracic and Cardiovascular Surgery Division, University of the Ryukyus, Okinawa 903-0215, Japan
A loss of heterozygosity (LOH) is a major cause of lung carcinogenesis, and it is considered to be related to tobacco smoking in central type lung cancer. We investigated the relationship between LOH in lung adenocarcinoma and tobacco smoking. In a consecutive series of 50 patients with lung adenocarcinoma who underwent a surgical resection, cancer tissue specimens and corresponding normal peripheral lung and central bronchial tissue specimens were analyzed for LOH at the regions of D3S1234 (FHIT), D3S1300 (FHIT), D9S171 (CDKN2), and D17S796 (p53) by polymerase chain reaction using four fluorescence-labeled dinucleotide markers. To examine how cells are influenced by smoking, the A549 cell line was exposed to benzo[a]pyrene (B[a]P) for 24 weeks and then was subjected to the above analysis. The LOH in cancer tissue was thus detected in four (17%) patients at D3S1234, six (14%) at D3S1300, and seven (18%) at D17S796, but no LOH was detected in any normal tissue specimens. The incidence of LOHs in cancer tissue specimens from active smokers was 21% at D3S1234, 11% at D3S1300, and 19% at D17S796, whereas that of LOHs from nonactive smokers was 0% at D3S1234, 19% at D3S1300, and 14% at D17S796. Analyzing the relationship between the pack-year index and the presence of LOH, a significant difference was found among the active smokers. Besides, in the A549 cell line exposed to B[a]P, LOH was de novo detected in one (D2S123) of the nine regions examined. The incidence of LOH could be influenced by tobacco smoking in lung adenocarcinoma, thus suggesting the presence of an important event in the carcinogenesis of this disease.
Key words: Loss of heterozygosity (LOH); Microsatellite marker; Non-small cell lung cancer; Tobacco smoking
Address correspondence to Ichiro Yoshino, M.D., Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Fukuoka 812-8582, Japan. Tel: +81-92-642-5466; Fax: +81-92-642-5482; E-mail: email@example.com
Combination Therapy of Personalized Peptide Vaccination and Low-Dose Estramustine Phosphate for Metastatic Hormone Refractory Prostate Cancer Patients: An Analysis of Prognostic Factors in the Treatment
Masanori Noguchi,1,3 Takashi Mine,2 Akira Yamada,2,3 Yayoi Obata,2 Kazumi Yoshida,2 Junko Mizoguchi,2 Mamoru Harada,2 Shigetaka Suekane,1 Kyogo Itoh,2,3 and Kei Matsuoka1
1Department of Urology, Kurume University School of Medicine,
Kurume University, Kurume, Japan
2Department of Immunology, Kurume University School of Medicine, Kurume University, Kurume, Japan
3Research Center of Innovative Cancer Therapy of The 21st Century Center of Excellence (COE) Program for Medical Science, Kurume University, Kurume, Japan
The aim of this study was to investigate prognostic factors of patients with metastatic hormone refractory prostate cancer (HRPC) under combined administration of personalized peptide vaccination and low-dose estramustine phosphate (EMP). From February 2001 to July 2004, 58 men with metastatic HRPC received the combination therapy of personalized peptide vaccination and low-dose EMP. Conducted immune monitorings for those patients were peptide-specific cytotoxic T lymphocyte (CTL) precursor analysis by interferon-γ production and peptide-reactive immunoglobulin G (IgG) by an enzyme-linked immunosorbent assay. Clinical responses and survival times were also evaluated. The combination therapy was well tolerated with no major adverse effects. Increased levels of CTL precursors and IgG responses to the vaccinated peptides were observed in 29 of 37 (78%) patients and in 36 of 41 (88%) patients tested, respectively. A prostate-specific antigen decline of at least 50% occurred in 24% of patients. The median survival time was 17 months (95% confidence interval, 12-25 months). Cox proportional hazards analysis showed that a low number of lymphocytes (p = 0.0075, odds ratio 2.700), a negative immunological activity response after the vaccination (p = 0.0185, odds ratio 2.658), and poor performance status (p = 0.0347, odds ratio 2.569) were independent predictors of disease death. These encouraging results show the need for further evaluation of the combination of personalized peptide vaccination and low dose of EMP for metastatic HRPC patients.
Key words: Prostate cancer; Immunotherapy; Cancer vaccine; Estramustine phosphate
Address correspondence to Masanori Noguchi, M.D., Ph.D., Department of Urology, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. Tel: +81-942-31-7572; Fax: +81-942-34-2605; E-mail: firstname.lastname@example.org