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Oncology Research/Anti-Cancer Drug Design, Volume 13, pp. 3-8
0965-0407/02 $20.00 + .00
Copyright © 2002 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Pigmentation in Melanomas: Changes Manifesting Underlying Oncogenic and Metabolic Activities

Ruth Halaban

Department of Dermatology, Yale University School of Medicine, New Haven, CT, 06520

Changes in pigmentation are frequently encountered in primary and metastatic melanocytic lesions. Pigmentation is determined by the activity of tyrosinase (TYR), the rate-limiting enzyme in melanin synthesis. Tyrosinase activity can be modulated at the genetic and/or epigenetic level. In this commentary I suggest that pigmentation can serve as an indicator for genetic and metabolic changes as follows. In TYR-negative, amelanotic melanomas cells, downregulation of TYR and other melanocyte-specific gene expression is likely to be mediated by dominantly acting oncogenes with impact on the transcriptional activity of the melanocyte-specific transcription factor Mitf. Ras and c-myc, shown to be active and upregulated in subclasses of melanoma tumors, have the potential to induce these changes. TYR-positive highly pigmented melanoma tumors are likely to reside in aerobic, well-vascularized microenvironment. In contrast, hypo- or amelanotic TYR-positive lesions suffer from reduced TYR activity due to an acidified microenvironment. These lesions might have encountered anaerobic conditions, and have adapted to the reduced oxygen by enhanced glycolysis, leading to extracellular acidification and activation of V-ATPase.

Key words: Pigmentation; Genetic changes; Metabolic changes; Tyrosinase

Address correspondence to Dr. Ruth Halaban, Yale University School of Medicine, Department of Dermatology, P.O. Box: 208059, 15 York Street, HRT 610, New Haven, CT 06520-8059. Tel: (203) 785-4352; Fax: (203) 785-7637; E-mail: ruth.halaban@yale.edu

Oncology Research/Anti-Cancer Drug Design, Volume 13, pp. 9-18
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Copyright © 2002 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Dose and Timing of Total-Body Irradiation Mediate Tumor Progression and Immunomodulation

Glen M. Miller,1 Eric H. Kajioka,2 Melba L. Andres,2 and Daila S. Gridleya2

1Department of Microbiology & Molecular Genetics and the 2Radiobiology Program, Department of Radiation Medicine, Loma Linda University and Medical Center, Loma Linda, CA

The major goal of this study was to examine the effects of total-body irradiation (TBI) on lung carcinoma progression and determine if changes in tumor growth could be correlated with radiation-induced alterations of immune system parameters. Lewis lung tumor cells were injected subcutaneously into syngeneic C57BL/6 mice that had been irradiated with a single 3.0 Gy dose of g-rays (60Co) at four time points either before or after tumor cell implantation. Subsequently, a second group of mice was irradiated 2 h prior to tumor injection with sequential doses of g-rays (0.46-2.66 Gy range). Assays were performed on blood and spleen from mice euthanized 16 days postimplantation. Tumor growth was consistently slower regardless of the timing of radiation exposure. However, dose of radiation influenced tumor growth delay. The preirradiated tumor-bearing mice had high CD4/CD8 T lymphocyte ratios along with increasing percentages of NKT cells in the blood supply with dose. Tumor-induced immunomodulation was also present, as evidenced by splenomegaly, low proliferative response to mitogens, and decreased spontaneous blastogenesis of leukocytes within the blood compared with normal values (P < 0.01). Anemia and thrombocytopenia were not observed with either tumor presence or irradiation. The present study demonstrates that a modest dose of TBI prior to tumor cell implantation resulted in a beneficial antitumor effect. A selective radiation-induced depletion of CD8+ T lymphocytes and changes in NKT cell percentages, correlated with findings from cytotoxicity assays, were indicative of a protumoricidal immune environment.

Key words: Total-body irradiation; Lung tumor; T lymphocytes; CD4/CD8 ratio; NKT cells

Address correspondence to Daila S. Gridley, Ph.D., Chan Shun Pavilion, Room A-1010, 11175 Campus Street, Loma Linda University School of Medicine, Loma Linda, CA 92354. Tel: (909) 558-8361; Fax: (909) 558-0825; E-mail: dgridley@dominion.llumc.edu

Oncology Research/Anti-Cancer Drug Design, Volume 13, pp. 19-24
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Copyright © 2002 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Exposure to Global System for Mobile Communication (GSM) Cellular Phone Radiofrequency Alters Gene Expression, Proliferation, and Morphology of Human Skin Fibroblasts

Stefania Pacini,1 Marco Ruggiero,2 Iacopo Sardi,1 Stefano Aterini,2 Franca Gulisano,3 and Massimo Gulisano1

1Department of Human Anatomy, Histology and Forensic Medicine, 2Department of Experimental Pathology and Oncology, and 3Department of Physics, University of Firenze, viale Morgagni 85, 50134 Firenze, Italy

Human skin fibroblasts were exposed to global system for mobile communication (GSM) cellular phone radiofrequency for 1 h. GSM exposure induced alterations in cell morphology and increased the expression of mitogenic signal transduction genes (e.g., MAP kinase kinase 3, G2/mitotic-specific cyclin G1), cell growth inhibitors (e.g., transforming growth factor-b), and genes controlling apoptosis (e.g., bax). A significant increase in DNA synthesis and intracellular mitogenic second messenger formation matched the high expression of MAP kinase family genes. These findings show that these electromagnetic fields have significant biological effects on human skin fibroblasts.

Key words: Nonionizing radiation; Gene expression; Cell growth; Cellular phone

Address correspondence to Prof. Marco Ruggiero, Department of Experimental Pathology and Oncology, Viale Morgagni 50, 50134 Firenze, Italy. Tel: +39 055 4282329; Fax: +39 055 4282333; E-mail: biolmol@yahoo.com

Oncology Research/Anti-Cancer Drug Design, Volume 13, pp. 25-35
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Copyright © 2002 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Verapamil Reverts Resistance to Drug-Induced Apoptosis in Ki-ras-Transformed Cells by Altering the Cell Membrane and the Mitochondrial Transmembrane Potentials

Daniela Spalletti-Cernia,1 Igea D'Agnano,2 Rosanna Sorrentino,1 Gabriella Zupi,3 Giancarlo Vecchio,1 Giuseppe Portella,1 and Paolo Laccetti1,4

1Dipartimento di Biologia e Patologia Cellulare e Molecolare & Centro di Endocrinologia ed Oncologia Sperimentale del CNR, Università degli Studi di Napoli Federico II, via S. Pansini no. 5, 80131 Napoli, Italy
2Istituto Tecnologie Biomediche, CNR, via Morgagni 30/E, 00161 Roma, Italy
3Laboratorio Chemioterapia Sperimentale Preclinica, Regina Elena, via delle Messi d'Oro no. 156, 00158 Roma, Italy
4Dipartimento di Chimica Biologica, Università degli Studi di Napoli Federico II, via Mezzocannone 16, 80134 Napoli, Italy

We have previously shown that in vivo ras-transformed cell lines display natural doxorubicin resistance compared with the normal cells and that such resistance is accompanied by a plasma membrane depolarization. In this article we first extend the analysis of doxorubicin effect to other ras-transformed cell lines, which are characterized by an increasing degree of malignant phenotype. Rat thyroid ras-transformed cells are markedly resistant to doxorubicin and the degree of drug resistance correlates with the degree of cell malignancy. The lower amount of drug accumulated inside the malignant and resistant cells is a consequence of their constitutive depolarized membrane potential and may account for their lack of drug-induced apoptosis. Verapamil, a known modulator of drug resistance, is able to decrease the resistance of all the malignant cell lines, initially causing a higher incorporation of doxorubicin as a consequence of its ability to hyperpolarize the membrane potential. In resistant cells, verapamil is also able to alter the mitochondrial membrane potential allowing apoptosis. In conclusion, these studies demonstrate that ras transformation induces the natural resistance to doxorubicin of the malignant cells. We suggest that the most malignant and resistant cells, of metastatic origin, could be preferentially destroyed by manipulation of their membrane properties, and we confirm the possibility of overcoming drug resistance by the administration of verapamil also in P-gp170-nonexpressing cells.

Key words: Apoptosis; Drug resistance; Membrane potentials; Metastases-derived thyroid cells; ras transformation; Verapamil

Address correspondence to Paolo Laccetti, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università degli Studi di Napoli Federico II, via S. Pansini no. 5, 80131 Napoli, Italy. Tel: 39-081-7463052; Fax: 39-081-7701016; E-mail: palaccet@ unina.it

Oncology Research/Anti-Cancer Drug Design, Volume 13, pp. 37-45
0965-0407/02 $20.00 + .00
Copyright © 2002 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Inhibition of Mouse Skin Tumor Promotion by Anti-Inflammatory Diarylheptanoids Derived From Alpinia oxyphylla Miquel (Zingiberaceae)

Kyung-Soo Chun,1 Kwang-Kyun Park,2 Jeewoo Lee,1 Myungshim Kang,1 and Young-Joon Surh1

1Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea
2Yonsei University College of Dentistry, Seoul 120-752, South Korea

Alpinia oxyphylla Miquel, which belongs to the ginger family (Zingiberaceae), has been used in Oriental herbal medicine. Our recent studies have revealed that the methanolic extract of A. oxyphylla suppresses mouse skin tumor promotion and induces apoptosis in cultured human promyelocytic leukemia cells. In the present work, we have assessed effects of yakuchinone A and yakuchinone B, phenolic diarylheptanoids derived from A. oxyphylla, on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation and epidermal ornithine decarboxylase (ODC) activity as well as on skin tumor promotion in female ICR mice. Thus, topical application of 2 or 6 mmol of the diarylheptanoids prior to each topical dose of TPA significantly ameliorated 7,12-dimethylbenz[a]anthracene-initiated mouse skin tumor formation. In parallel with suppression of tumor promotion, topically applied yakuchinone A and B markedly inhibited TPA-induced epidermal ODC activity and ODC mRNA expression. In another experiment, yakuchinone A and B reduced production of tumor necrosis factor-a in TPA-stimulated mouse skin. Furthermore, both compounds inhibited the TPA-induced expression of cyclooxygenase-2 at both transcriptional and translational levels. These findings indicate that pungent diarylheptanoids from A. oxyphylla Miquel have an antitumor promotional activity that might be related to their anti-inflammatory properties.

Key words: Alpinia oxyphylla Miquel; Antitumor promotion; Diarylheptanoids; Mouse skin tumor promotion; Yakuchinone

Address correspondence to Prof. Young-Joon Surh, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, South Korea. Tel: +82 2 880-7845; Fax: +82 2 874-9775; E-mail: surh@plaza.snu.ac.kr

Oncology Research/Anti-Cancer Drug Design, Volume 13, pp. 47-54
0965-0407/02 $20.00 + .00
Copyright © 2002 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Synergistic Enhancement of the Antitumor Effect of Taxol by the Bioreductive Compound NLCQ-1, In Vivo: Comparison With Tirapazamine

Maria V. Papadopoulou, Ming Ji, and William D. Bloomer

The Radiation Medicine Institute at Evanston Northwestern Healthcare, 2650 Ridge Avenue, Evanston, IL 60201

The antitumor effect of taxol was investigated in combination with the bioreductive compounds NLCQ-1 or tirapazamine (TPZ), in vivo. The EMT6/BALB/c and SCCVII/C3H murine tumor models were used. All drugs were given by IP injection: NLCQ-1 at 10 mg/kg (28% of its LD50), TPZ at 30 or 23 mg/kg (38% or 28% of its LD50, respectively), and taxol up to 25 mg/kg. Dose modification factors (DMF) were calculated at the optimal administration intervals for potentiation of taxol by NLCQ-1/TPZ, by using the in vivo-in vitro assay as the endpoint. Bone marrow toxicity studies were performed in parallel by using a modified CFU-GM assay. A schedule-dependent potentiation of taxol was observed with either hypoxic cytotoxin and in both tumor models. The percentage of tumor cells, P, that were killed beyond additivity was 59.2 and 29.5 when NLCQ-1 was administered 1-3 h after, and TPZ 3 h before taxol, respectively, in the EMT6/BALB/c model. The P values in the SCCVII/C3H model were 31.0 and 24.6 for NLCQ-1 and TPZ, respectively, when either of them was administered ca. 2 h after taxol. At the above time schedules, therapeutic indexes [ThI = DMFT/INFTDMFBM, where DMFT and DMFBM are the DMF values for the antitumor effect and bone marrow toxicity, respectively] of 2.5 and 2.0 were obtained by NLCQ-1 in the EMT6 and SCCVII tumors, respectively, whereas a ThI of 1.2 was obtained by TPZ in both type of tumors. These results suggest a potential clinical use of NLCQ-1 as a potentiator of taxol against solid tumors possessing hypoxic regions.

Key words: NLCQ-1; Tirapazamine; Taxol; Synergism; Hypoxic cytotoxins

Address correspondence to Maria V. Papadopoulou, Evanston Northwestern Healthcare, Department of Radiation Medicine, 2650 Ridge Avenue, Evanston, IL 60201. Tel: (847) 570-2262; Fax: (847) 570-1878; E-mail: m-papadopoulou@nwu.edu

Oncology Research/Anti-Cancer Drug Design, Volume 13, pp. 55-59
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Copyright © 2002 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Epithelioid Granulomas as Main Clinical Manifestation at the Outset of Non-Hodgkin's Lymphoma: Report of Two Cases

Roberto Lerza,1 Emanuela Schenone,1 Bianca Paola Barsotti,1 Marco Botta,1 Eleonora Arboscello,1 Mauro Truini,2 Giuseppe Bogliolo,1 and Ivo Pannacciulli1

1Clinica di Medicina Interna 2, Dipartimento di Medicina Interna, Università di Genova, Genova, Italy
2Servizio di Anatomia Patologica, Azienda Ospedaliera S. Martino, Genova, Italy

This article describes two cases of malignant lymphoma in which the finding of a striking epithelioid granulomatosis was the main clinical manifestation at the outset of the patients' history. Despite some suggestive clinical and laboratory data, the final diagnosis of lymphoproliferative disorder was made only after repeated histological studies in both patients. Although the association between a severe granulomatous reaction and a B-cell neoplasm is rare, the latter should be taken into account as a possible primary disease. The pathogenetic mechanisms postulated by the literature as the cause of granulomatous reactions in lymphoproliferative disorders are reported and discussed in relation to the two cases.

Key words: Granulomatosis; Non-Hodgkin's lymphoma; Lymphoma

Address correspondence to Prof. Ivo Pannacciulli, M.D., Dipartimento di Medicina Interna (DI.M.I.), Università degli Studi di Genova, Viale Benedetto XV no. 6, 16132 Genova, Italy. Tel: 0039 010 3537939; Fax: 0039 010 352324; E-mail: imp@unige.it