|ognizant Communication Corporation|
AN INTERNATIONAL JOURNAL
INCORPORATING ANTI-CANCER DRUG DESIGN
VOLUME 13, NUMBER 4
Oncology Research/Anti-Cancer Drug Design, Volume 13, pp. 191-197
0965-0407/03 $20.00 + .00
Copyright © 2003 Cognizant Comm. Corp.
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Nadine Costes,1 Abdelhakim Elomri,2 Hanh Dufat,1 Sylvie Michel,1 Elisabeth Seguin,2 Michel Koch,1 François Tillequin,1 Bruno Pfeiffer,3 Pierre Renard,3 Stéphane Léonce,4 and Alain Pierré4
1Laboratoire de Pharmacognosie de l'Université René
Descartes, U.M.R./C.N.R.S. No. 8638, Faculté des Sciences Pharmaceutiques
et Biologiques, 4, Avenue de l'Observatoire, F-75006 Paris, France
2Laboratoire de Pharmacognosie de l'Université de Rouen-Haute Normandie, Faculté de Pharmacie, 22, Boulevard Gambetta, F-76183 Rouen Cedex, France
3Les Laboratoires Servier, 1 rue Carle Hébert, F-92415 Courbevoie Cedex, France
4Institut de Recherche Servier, 11 rue des Moulineaux, F-92150 Suresnes, France
The novel 6-dialkylaminoalkylamino-3,3,12-trimethyl-3,12-dihydro-7H-pyrano[2,3-c]acridine-7-ones 5-11 and their benzo[b]pyrano[2,3-h]acridine-7-one counterparts 12-18 were prepared by treatment of acronycine (1) or benzo[b]acronycine (4) with an excess of the appropriate dialkylaminoalkylamine. In both series, the introduction of a dialkylaminoalkylamino side chain at position 6 resulted in a significant increase of the cytotoxic activity against L1210 cells when compared with the parent compounds bearing a methoxy group, accompanied with an increased potency to arrest cells in the G2 + M phases of the cell cycle.
Key words: Acronycine; Benzo[b]acronycine; 6-Dialkylaminoalkylamino side chains; Cytotoxicity
Address correspondence to François Tillequin, Laboratoire de Pharmacognosie de l'UniversitéRené Descartes, U.M.R./C.N.R.S. No. 8638, Faculté des Sciences Pharmaceutiques et Biologiques, 4, Avenue de l'Observatoire, F-75006 Paris, France. E-mail: firstname.lastname@example.org
Synthesis and Biological Evaluation of Novel bis-Aziridinylnaphthoquinone Derivatives
Sheng-Tung Huang, Hsien-Shou Kuo, Chun-Mao Lin, Hsin-Da Tsai, Yi-Chen Peng, Chien-Tsu Chen, and Yuh-Ling Lin
Department of Biochemistry, Taipei Medical University, Taipei, Taiwan, 250 Wu Hsing Street Taipei, Taiwan 110, ROC
A series of bis-aziridinylnaphthoquinone derivatives has been prepared. The cytotoxic activities and DNA alkylation abilities of these synthetic bis-aziridinylnaphthoquinone derivatives were investigated. They displayed significant cytotoxicity against human carcinoma cell lines and weak cytotoxic activities against HL60 and skin fibroblast (SF). The bis-aziridinylnaphthoquinone 1a was the most potent agent among those tested, with an LD50 value of 0.57 mM against the BC-M1 cell line. It exhibited the weakest activity against SF and HL60 with LD50 values of 5.67 and 20.1 mM, respectively, and it was able to alkylate DNA after chemical reduction in vitro. The analogues without aziridinyl moiety 2a and 3a lack DNA alkylation abilities.
Key words: bis-Aziridinylnaphthoquinone derivatives; DNA alkylation; Tumor hypoxia
Address correspondence to Yuh-Ling Lin, Department of Biochemistry, Taipei Medical University, Taipei, Taiwan, 250 Wu Hsing Street, Taipei, Taiwan 110, ROC. Tel: 886-2-2736-1661, ext. 3159; Fax: 886-2-27846579; E-mail: email@example.com
Yïldïz Dinçer,1 Tülay Akçay,1 Osman B. Tortum,2 Zeynep Alademir,1 Sinan Önen,3 and Gülen Dogusoy4
1Department of Biochemistry, 2Department of General Surgery, 3Department of Biophysics, and 4Department of Pathology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, 34300-Turkey
O6-Methylguanine DNA methyltransferase (O6-MGMT) reverses DNA alkylation damage produced by alkylating agents. O6-MGMT is also a major determinant of cellular resistance to adjuvant chemotherapy with alkylating drugs. O6-MGMT activity was measured in samples from patients with gastric cancer, including tumor, adjacent normal appearing mucosa, and peripheral blood leukocytes (PBL). O6-MGMT activity of PBL from healthy individuals was evaluated as control. There was no significant difference between controls and patients for O6-MGMT activity in PBL. O6-MGMT activity was significantly increased in tumor tissue. Tumor O6-MGMT activity was found to be independent from tumor subgroups and tumor grade. A positive correlation was determined between O6-MGMT activity in tumor and in circulating PBL. The results indicate that O6-MGMT, a defense protein against alkylating agent-mediated carcinogenesis, increased in gastric tumors. This may explain the low response rate to drug combinations, including chloroethylnitrosoureas, exhibited by patients with gastric cancer.
Key words: Gastric tumors; Alkylating agents; DNA repair; Drug resistance; O6-methylguanine DNA methyltransferase
Address correspondence to Yïldïz Dinçer, Cebesoy Sok., Eko Tek, B Blok No: 5/3 Sahrayï Cedid, Erenköy, Istanbul, Turkey. Tel: 90 216 3857508; Fax: 90 212 2726730; E-mail: firstname.lastname@example.org
Maud Boucaud,1,2 Frédéric Pinguet,2 Stéphane Culine,3 Sylvain Poujol,2 Cécile Astre,2 Roberto Gomeni,1 and Françoise Bressolle1,2*
1Clinical Pharmacokinetic Laboratory, Faculty of Pharmacy,
University Montpellier I, 15 Avenue Ch. Flahault, BP 14 491, 34093 Montpellier
Cedex 5, France
2Oncopharmacology Department, Pharmacy service, Val d'Aurelle Anticancer Centre, parc Euromédecine, Montpellier, France
3Department of Medicine, Val d'Aurelle Anticancer Centre, parc Euromédecine, Montpellier, France
The purpose of this study was to develop a pharmacokinetic model simultaneously accounting for topotecan concentrations in plasma and saliva. Thirteen patients with metastatic epithelial ovarian cancer received topotecan. During the first and the second courses of treatment, each patient underwent pharmacokinetic evaluation. Data were analyzed using the nonlinear mixed-effect model program. The saliva concentrations were associated to a peripheral compartment while the central compartment described the plasma concentration time course. Thus, a three-compartment model was used; the basic parameters were: total clearance (CL), initial volume of distribution (V1), transfer rate constants (k12/k21 and k13/k31). The interoccasion variability was taken into account in the model. Data analysis was performed using a three-step approach; in step 2, a close relationship was found between creatinine CL and topotecan CL. The inclusion of this second stage model significantly improved the fit. Large interindividual variability in pharmacokinetic parameters occurred (CL varied from 10.4 to 23 L/h) while interoccasion variability was limited (6%). Seven additional courses were used for model validation. A limited sampling strategy using Bayesian estimation based on two sampling times (saliva at 25 min and plasma plus saliva at 8.5 h after the start of infusion) was developed. This study shows that salivary concentrations can be effectively used for drug monitoring.
Key words: Topotecan; Plasma; Saliva; Population pharmacokinetics; Limited sampling strategy
Address correspondence to Dr. Françoise Bressolle, Ph.D., Laboratoire de Pharmacocinétique Clinique, Faculté de Pharmacie, B.P. 14491, 34093 Montpellier Cedex 5, France. Tel/Fax: + 33-4-67-54-80-75; E-mail: FBressolle@aol.com
*Present address: GlaxoSmithKline, Verona, Italy.
Synthesis and Antitumor Cytotoxicity Evaluation of Novel Pyrrolo[2,1-c][1,4]benzodiazepine Imidazole Containing Polyamide Conjugates
Rohtash Kumar and J. William Lown
Department of Chemistry, University of Alberta, Edmonton, AB, Canada, T6G 2G2
The design, synthesis, and biological evaluation of novel C-8 linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD)-imidazole polyamide conjugates (1-5) are described that involve mercuric chloride-mediated cyclization of the corresponding amino diethyl thioacetals. The compounds were prepared with varying numbers of imidazole- and pyrrole-containing polyamides in order to probe the structural requirements for optimal in vitro antitumor activity. These compounds were tested against a panel of human cancer cells by the National Cancer Institute, demonstrating that the compounds exhibited a higher level of cytotoxic activity than the existing natural and synthetic pyrrolo[2,1-c][1,4]benzodiazepines. The data presented show that the length of the polyamides and also the type of heterocycle play important roles in this series of compounds for anticancer activity. Compounds 1, 2, 3, and 5 have significant cytotoxic activity against the various types of cancer cell lines. It appears that cytotoxic activity is related to both the length and the heterocycles of the polyamides. Compound 1 exhibited a wide spectrum of anticancer activities against all cell lines in nine cancer panels and was especially effective against colon cancer, melanoma, and renal cancer and breast cancer; however, compound 4 did not exhibit any significant anticancer activity. This study found that PBD-imidazole polyamide conjugates are highly cytotoxic against many human cancer cell lines in comparison with the PBD-pyrrole polyamide conjugates.
Key words: Cytotoxicity; Polyamide; Pyrrolo[2,1-c][1,4]benzodiazepines; DNA minor groove binders; PBD-polyamide conjugate
Address correspondence to J. William Lown, Department of Chemistry, University of Alberta, Edmonton, AB, Canada,T6G2G2. Tel: (780) 492-3646; Fax: (780) 492-8231; E-mail: email@example.com
Lymphokine-Activated Killer Cells Can Kill Target Cells Not Only by Early Killing But Also by Late Killing, and the Late Killing Level Against Autotumor Cell Line
Fumio Komatsu and Kiyomi Ishiguro
Department of Clinical Physiology, Kagawa Nutrition University, 3-9-21 Chiyoda, Sakado, Saitama 350-0288, Japan
Generally, lymphokine-activated killer (LAK) cells kill target cells early after the LAK cells adhere to them. In this study, we describe that LAK cells can also kill at a later time, such as 24-96 h. LAK cells were generated from a cancer patient and healthy volunteers. As target cells, the patient's autotumor cell line H41 was used. When LAK cells were added to the target cells in a culture well, the LAK cells killed the target cells by cell-cell adhesion within 1-4 h (early killing), but not all cells were killed. The LAK cells were then removed. However, the remaining cells ultimately died 24-96 h later (late killing). The late killing was different from the early killing because numerous granules and vacuoles appeared in the cytoplasm. The late killing was not induced by adding supernatant of the LAK cell culture, suggesting that LAK-target cell contact may be necessary for the killing. The cell injury was inhibited by 3-methyladenine (lysosome inhibitor). It suggests that the vacuoles may be caused by activated lysosome. The patient's LAK cells induced late killing at high levels. There was a high percentage of CD8+CD16+ cells in the peripheral blood lymphocytes (PBL). This subset induced late killing more effectively than the CD8-CD16+ subset. Killing was more conspicuous against H41 than against allogeneic cell line T98G. This type of killing is noteworthy for understanding of killing mechanism of LAK cells.
Key words: LAK cells; Early killing; Cell-cell adhesion killing; Late killing; Autotumor cell line; Lysosome
Address correspondence to Fumio Komatsu, M.D., Department of Clinical Physiology, Kagawa Nutrition University, 3-9-21 Chiyoda, Sakado, Saitama 350-0288, Japan. Tel & Fax: 0081-49-282-3702.