Gemcitabine: A critical nucleoside for cancer therapy

Current Medicinal Chemistry

Volumn 19, Issue 7, 2012, Pages 1076-1087

  Gesto, D S ^a   Cerqueira, N M F S A ^a   Fernandes, P A ^a   Ramos, M J ^a  

^a UNIVERSITY OF PORTO   (Portugal)

Author keywords

Apoptosis; Deoxycytidine kinase; Gemcitabine; Mechanism of action; Nucleoside transporters; Ribonucleotide reductase; Self potentiation

Indexed keywords

CAPECITABINE; CARBOPLATIN; CISPLATIN; CYTARABINE; DEOXYCYTIDINE; DEOXYCYTIDINE KINASE; DOCETAXEL; ERLOTINIB; FLUOROURACIL; GEMCITABINE; IRINOTECAN; NUCLEOSIDE DERIVATIVE; NUCLEOTIDE DERIVATIVE; PACLITAXEL;

ACUTE GRANULOCYTIC LEUKEMIA; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CANCER CHEMOTHERAPY; CANCER COMBINATION CHEMOTHERAPY; CELL CYCLE ARREST; CELL MEMBRANE TRANSPORT; CHRONIC MYELOID LEUKEMIA; CYTOTOXICITY; DNA SYNTHESIS INHIBITION; DRUG ACTIVATION; DRUG DNA INTERACTION; DRUG ELIMINATION; DRUG INACTIVATION; DRUG MECHANISM; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TRANSPORT; HODGKIN DISEASE; HUMAN; LUNG NON SMALL CELL CANCER; MULTIPLE MYELOMA; NONHODGKIN LYMPHOMA; NONHUMAN; OVARY CANCER; PHOSPHORYLATION; REVIEW; SARCOMA;

EID: 84858173640     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/092986712799320682     Document Type: Review

References (108)

1. Hertel, L.; Kroin, J.; Misner, J.; Tustin, J., Synthesis of 2-deoxy-2, 2- difluoro-D-ribose and 2-deoxy-2, 2'-difluoro-D-ribofuranosyl nucleosides. The Journal of Organic Chemistry 1988, 53 (11), 2406-2409.
2. Delong, D. C.; Hertel, L. W.; Tang, J.; Kroin, J. S.; Wilson, J. D.; Terry, J.; Lavender, J. F., Antiviral acvtivity of 2', 2'-difluorodeoxycytidine. Am SOC Microbiol Abstracts 1986.
3. Hertel, L. W.; Boder, G. B.; Kroin, J. S.; Rinzel, S. M.; Poore, G. A.; Todd, G. C.; Grindey, G. B., Evaluation of the Antitumor-Activity of Gemcitabine (2',2'-Difluoro-2'-Deoxycytidine). Cancer Research 1990, 50 (14), 4417-4422.
4. Boven, E.; Schipper, H.; Erkelens, C. A. M.; Hatty, S. A.; Pinedo, H. M., The Influence of the Schedule and the Dose of Gemcitabine on the Antitumor Efficacy in Experimental Human Cancer. British Journal of Cancer 1993, 68 (1), 52-56. (Pubitemid 23178550)
5. Braakhuis, B. J. M.; Vandongen, G. A. M. S.; Vermorken, J. B.; Snow, G. B., Preclinical Invivo Activity of 2',2'-Difluorodeoxycytidine (Gemcitabine) against Human Head and Neck-Cancer. Cancer Research 1991, 51 (1), 211-214.
6. Fukuoka, M.; Takada, M.; Yokoyama, A.; Kurita, Y.; Niitani, H., Phase II studies of gemcitabine for non-small cell lung cancer in Japan. Semin Oncol 1997, 24 (2 Suppl 7), S7-42-S7-46.
7. Shepherd, F. A.; Abratt, R. P.; Anderson, H.; Gatzemeier, U.; Anglin, G.; Iglesias, J., Gemcitabine in the treatment of elderly patients with advanced non-small cell lung cancer. Semin Oncol 1997, 24 (2 Suppl 7), S7-50-S7-55.
8. Rosell, R.; Sanchez, J. M.; Taron, M.; O'Brate, A.; Gutierrez, J. L.; Monzo, M.; Felip, E.; Sanchez, J. J.; Alberola, V., Novel approaches in the treatment of non-small-cell lung cancer. Oncology-New York 2001, 15 (3), 52-60. (Pubitemid 33739206)
9. Scarpati, M. D.; Vicidomini, G.; Santini, M., Gemcitabine and small cell lung cancer. Lung Cancer 2001, 34 (2), 313-314. (Pubitemid 33010808)
10. [Anon], Gemcitabine: The emerging standard in the treatment of lung cancer. Oncology-New York 2001, 15 (3), 4-4.
11. Prost, P.; Ychou, M.; Azria, D., Gemcitabine and pancreatic cancer. Bulletin Du Cancer 2002, 89, S91-S95.
12. Feliu, J.; Alvarez, M. P. L.; Jaraiz, M. A.; Constenla, M.; Vicent, J. M.; Belon, J.; Gomez, L. L.; de Castro, J.; Dorta, J.; Baron, M. G.; Grp, O. C., Phase II trial of gemcitabine and UFT modulated by leucovorin in patients with advanced pancreatic carcinoma. Cancer 2000, 89 (8), 1706-1713.
13. Rauch, D. P.; Maurer, C. A.; Aebi, S.; Pampallona, S.; Friess, H.; Ludwig, C. U.; Buchler, M. W.; Borner, M. M., Activity of gemcitabine and continuous infusion fluorouracil in advanced pancreatic cancer. Oncology 2001, 60 (1), 43-48. (Pubitemid 32041430)
14. Sherman, W. H.; Fine, R. L., Combination gemcitabine and docetaxel therapy in advanced adenocarcinoma of the pancreas. Oncology 2001, 60 (4), 316-321. (Pubitemid 32623446)
15. Kozuch, P.; Petryk, M.; Bruckner, H. W., A comprehensive update on the use of chemotherapy for metastatic pancreatic adenocarcinoma. Hematology- Oncology Clinics of North America 2002, 16 (1), 123-+.
16. Plate, J. M. D.; Plate, A. A. E.; Shott, S.; Bograd, S.; Harris, J. E., Effect of gemcitabine on immune cells in subjects with adenocarcinoma of the pancreas. Cancer Immunology Immunotherapy 2005, 54 (9), 915-925. (Pubitemid 40991334)
17. [Anon], Gemcitabine active in patients with metastatic breast cancer. Oncology-New York 2001, 15 (7), 917-917.
18. Adjei, A. A., Gemcitabine and pemetrexed disodium in treatment breast cancer. Oncology-New York 2001, 15 (2), 34-37. (Pubitemid 33739160)
19. Pautier, P.; Gutierrez, M.; Lhomme, C., Gemcitabine in the treatment of epithelial ovarian cancer. Bulletin Du Cancer 2002, 89, S115-S119.
20. Sevelda, P., Second-line therapy of ovarian carcinoma. Onkologie 2000, 23 (6), 593-596. (Pubitemid 32046060)
21. Barocas, D. A.; Clark, P. E., Bladder cancer. Current Opinion in Oncology 2008, 20 (3), 307-314. (Pubitemid 351507552)
22. Ellison, R. R.; Carey, R. W.; Holland, J. F., Continuous Infusions of Arabinosyl Cytosine in Patients with Neoplastic Disease. Clinical Pharmacology & Therapeutics 1967, 8 (6), 800-&.
23. Pankiewicz, K. W., Fluorinated nucleosides. Carbohydrate Research 2000, 327 (1-2), 87-105.
24. Duschinsky, R.; Pleven, E.; Heidelberger, C., The Synthesis of 5- Fluoropyrimidines. Journal of the American Chemical Society 1957, 79 ( 16), 4559-4560.
25. Carson, D. A.; Wasson, D. B.; Esparza, L. M.; Carrera, C. J.; Kipps, T. J.; Cottam, H. B., Oral Antilymphocyte Activity and Induction of Apoptosis by 2-Chloro-2'-Arabino-Fluoro-2'-Deoxyadenosine. Proceedings of the National Academy of Sciences of the United States of America 1992, 89 (7), 2970-2974.
26. Takahashi, T.; Kanazawa, J.; Akinaga, S.; Tamaoki, T.; Okabe, M., Antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine, a novel deoxyadenosine analog, against human colon tumor xenografts by oral administration. Cancer Chemotherapy and Pharmacology 1998, 43 (3), 233-240.
27. Burchenal, J. H.; Cunningham, K. C.; Pancoast, T. C.; Robins, R. K., The Anti-Leukemic Activity of 2-B-D-Ribofuranosyl-Thiazole 4-Carboxamide (Rtc) in Mice as Affected by Purines, Nicotinamide, and Polyamine Pathway Inhibitors. Proceedings of the American Association for Cancer Research 1983, 24 (Mar), 304-304.
28. Kaye, S. B., Gemcitabine - Current Status of Phase-I and Phase-Ii Trials. Journal of Clinical Oncology 1994, 12 (8), 1527-1531. (Pubitemid 24244984)
29. Lund, B.; Kristjansen, P. E. G.; Hansen, H. H., Clinical and Preclinical Activity of 2′,2′-Difluorodeoxycytidine (Gemcitabine). Cancer Treatment Reviews 1993, 19 (1), 45-55. (Pubitemid 23087952)
30. Grunewald, R.; Kantarjian, H.; Du, M.; Faucher, K.; Tarassoff, P.; Plunkett, W., Gemcitabine in Leukemia - a Phase-I Clinical, Plasma, and Cellular Pharmacology Study. Journal of Clinical Oncology 1992, 10 (3), 406-413.
31. Abbruzzese, J. L.; Grunewald, R.; Weeks, E. A.; Gravel, D.; Adams, T.; Nowak, B.; Mineishi, S.; Tarassoff, P.; Satterlee, W.; Raber, M. N.; Plunkett, W., A Phase-I Clinical, Plasma, and Cellular Pharmacology Study of Gemcitabine. Journal of Clinical Oncology 1991, 9 (3), 491-498.
32. Heinemann, V.; Hertel, L. W.; Grindey, G. B.; Plunkett, W., Comparison of the Cellular Pharmacokinetics and Toxicity of 2',2'-Difluorodeoxycytidine and 1-Beta-D-Arabinofuranosylcytosine. Cancer Research 1988, 48 (14), 4024-4031.
33. Hui, Y. F.; Reitz, J., Gemcitabine: A cytidine analogue active against solid tumors. American Journal of Health-System Pharmacy 1997, 54 (2), 162-170. (Pubitemid 27058210)
34. Kong, W.; Engel, K.; Wang, J., Mammalian nucleoside transporters. Current Drug Metabolism 2004, 5 (1), 63-84. (Pubitemid 38279408)
35. Archer, R. G.; Pitelka, V.; Hammond, J. R., Nucleoside transporter subtype expression and function in rat skeletal muscle microvascular endothelial cells. Br J Pharmacol 2004, 143 (1), 202-14. (Pubitemid 39280040)
36. Hyde, R. J.; Cass, C. E.; Young, J. D.; Baldwin, S. A., The ENT family of eukaryote nucleoside and nucleobase transporters: recent advances in the investigation of structure/function relationships and the identification of novel isoforms. Mol Membr Biol 2001, 18 (1), 53-63. (Pubitemid 32521597)
37. Baldwin, S. A.; Mackay, J. R.; Cass, C. E.; Young, J. D., Nucleoside transporters: molecular biology and implications for therapeutic development. Molecular Medicine Today 1999, 5 (5), 216-224. (Pubitemid 29282300)
38. Mackey, J. R.; Mani, R. S.; Selner, M.; Mowles, D.; Young, J. D.; Belt, J. A.; Crawford, C. R.; Cass, C. E., Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res 1998, 58 (19), 4349-57. (Pubitemid 28450036)
39. Mackey, J. R.; Yao, S. Y.; Smith, K. M.; Karpinski, E.; Baldwin, S. A.; Cass, C. E.; Young, J. D., Gemcitabine transport in xenopus oocytes expressing recombinant plasma membrane mammalian nucleoside transporters. J Natl Cancer Inst 1999, 91 (21), 1876-81.
40. Ritzel, M. W. L.; Ng, A. M. L.; Yao, S. Y. M.; Graham, K.; Loewen, S. K.; Smith, K. N.; Ritzel, R. G.; Mowles, D. A.; Carpenter, P.; Chen, X. Z.; Karpinski, E.; Hyde, R. J.; Baldwin, S. A.; Cass, C. E.; Young, J. D., Molecular identification and characterization of novel human and mouse concentrative Na+-nucleoside cotransporter proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides (system cib). Journal of Biological Chemistry 2001, 276 (4), 2914-2927.
41. Johansson, M.; Brismar, S.; Karlsson, A., Human deoxycytidine kinase is located in the cell nucleus. Proceedings of the National Academy of Sciences of the United States of America 1997, 94 (22), 11941-11945. (Pubitemid 27467821)
42. Sabini, E.; Ort, S.; Monnerjahn, C.; Konrad, M.; Lavie, A., Structure of human dCK suggests strategies to improve anticancer and antiviral therapy. Nature Structural Biology 2003, 10 (7), 513-519. (Pubitemid 36792901)
43. Peters, G. J., Deoxynucleoside Analogs in Cancer Therapy. 1st ed.; Humana Press Inc.: New Jersey, 2006.
44. Bouffard, D. Y.; Laliberte, J.; Momparler, R. L., Kinetic-Studies on 2′,2′- Difluorodeoxycytidine (Gemcitabine) with Purified Human Deoxycytidine Kinase and Cytidine Deaminase. Biochemical Pharmacology 1993, 45 (9), 1857-1861. (Pubitemid 23150977)
45. Wang, L.; Munch-Petersen, B.; Sjoberg, A. H.; Hellman, U.; Bergman, T.; Jornvall, H.; Eriksson, S., Human thymidine kinase 2: molecular cloning and characterisation of the enzyme activity with antiviral and cytostatic nucleoside substrates. Febs Letters 1999, 443 (2), 170-174. (Pubitemid 29078626)
46. Eriksson, S.; Kierdaszuk, B.; Munchpetersen, B.; Oberg, B.; Johansson, N. G., Comparison of the Substrate Specificities of Human Thymidine Kinase-1 and Kinase-2 and Deoxycytidine Kinase toward Antiviral and Cytostatic Nucleoside Analogs. Biochemical and Biophysical Research Communications 1991, 176 (2), 586-592.
47. Vanhaperen, V. W. T. R.; Veerman, G.; Eriksson, S.; Boven, E.; Stegmann, A. P. A.; Hermsen, M.; Vermorken, J. B.; Pinedo, H. M.; Peters, G. J., Development and Molecular Characterization of a 2′,2′- Difluorodeoxycytidineresistant Variant of the Human Ovarian-Carcinoma Cell-Line A2780. Cancer Research 1994, 54 (15), 4138-4143.
48. Bergman, A. M.; Munch-Petersen, B.; Jensen, P. B.; Sehested, M.; Veerman, G.; Voorn, D. A.; Smid, K.; Pinedo, H. M.; Peters, G. J., Collateral sensitivity to gemcitabine (2 ',2 ' -difluorodeoxycytidine) and cytosine arabinoside of daunorubicin- and VM-26-resistant variants of human small cell lung cancer cell lines. Biochemical Pharmacology 2001, 61 (11), 1401-1408. (Pubitemid 32452356)
49. Nielsen, S. E.; Munchpetersen, B.; Mejer, J., Increased Ratio between Deoxycytidine Kinase and Thymidine Kinase-2 in Cll Lymphocytes Compared to Normal Lymphocytes. Leukemia Research 1995, 19 (7), 443-447.
50. Nielsen, S. E.; Munchpetersen, B.; Mejer, J., Elevated ratio between deoxycytidine kinase and thymidine kinase 2 in cll lymphocytes compared to control cells. Purine and Pyrimidine Metabolism in Man Viii 1994, 370, 257-259
51. Hsu, C. H.; Liou, J. Y.; Dutschman, G. E.; Cheng, Y. C., Phosphorylation of cytidine, deoxycytidine, and their analog monophosphates by human UMP/CMP kinase is differentially regulated by ATP and magnesium. Molecular Pharmacology 2005, 67 (3), 806-814.
52. Liou, J. Y.; Dutschman, G. E.; Lam, W.; Jiang, Z. L.; Cheng, Y. C., Characterization of human UMP/CMP kinase and its phosphorylation of Dand L-form deoxycytidine analogue monophosphates. Cancer Research 2002, 62 (6), 1624-1631.
53. Lacombe, M. L.; Milon, L.; Munier, A.; Mehus, J. G.; Lambeth, D. O., The human Nm23/nucleoside diphosphate kinases. Journal of Bioenergetics and Biomembranes 2000, 32 (3), 247-258.
54. Gonin, P.; Xu, Y. W.; Milon, L.; Dabernat, S.; Morr, M.; Kumar, R.; Lacombe, M. L.; Janin, J.; Lascu, I., Catalytic mechanism of nucleoside diphosphate kinase investigated using nucleotide analogues, viscosity effects, and X-ray crystallography. Biochemistry 1999, 38 (22), 7265-7272.
55. Plunkett, W.; Huang, P.; Xu, Y. Z.; Heinemann, V.; Grunewald, R.; Gandhi, V., Gemcitabine - Metabolism, Mechanisms of Action, and Self-Potentiation. Seminars in Oncology 1995, 22 (4), 3-10.
56. Neff, T.; Blau, A., Forced expression of cytidine deaminase confers resistance to cytosine arabinoside and gemcitabine. Exp Hematol 1996, 24 (11), 1340-1346.
57. Eliopoulos, N.; Cournoyer, D.; Momparler, R. L., Drug resistance to 5-aza- 2′-deoxycytidine, 2′,2′-difluorodeoxycytidine, and cytosine arabinoside conferred by retroviral-mediated transfer of human cytidine deaminase cDNA into murine cells. Cancer Chemother Pharmacol 1998, 42 (5), 373-8. (Pubitemid 28430367)
58. Hunsucker, S. A.; Spychala, J.; Mitchell, B. S., Human cytosolic 5′- nucleotidase I: characterization and role in nucleoside analog resistance. J Biol Chem 2001, 276 (13), 10498-504.
59. Mazzon, C.; Rampazzo, C.; Scaini, M. C.; Gallinaro, L.; Karlsson, A.; Meier, C.; Balzarini, J.; Reichard, P.; Bianchi, V., Cytosolic and mitochondrial deoxyribonucleotidases: activity with substrate analogs, inhibitors and implications for therapy. Biochem Pharmacol 2003, 66 (3), 471-9. (Pubitemid 36937032)
60. Heinemann, V.; Xu, Y. Z.; Chubb, S.; Sen, A.; Hertel, L. W.; Grindey, G. B.; Plunkett, W., Cellular Elimination of 2',2'-Difluorodeoxycytidine 5′- Triphosphate - a Mechanism of Self-Potentiation. Cancer Research 1992, 52 (3), 533-539.
61. Braithwaite, D. K.; Ito, J., Compilation, alignment, and phylogenetic relationships of DNA polymerases. Nucleic Acids Res 1993, 21 (4), 787-802. (Pubitemid 23152983)
62. Huang, P.; Chubb, S.; Hertel, L. W.; Grindey, G. B.; Plunkett, W., Action of 2′,2′-difluorodeoxycytidine on DNA synthesis. Cancer Res 1991, 51 (22), 6110-7.
63. Achanta, G.; Pelicano, H.; Feng, L.; Plunkett, W.; Huang, P., Interaction of p53 and DNA-PK in response to nucleoside analogues: potential role as a sensor complex for DNA damage. Cancer Res 2001, 61 (24), 8723-9. (Pubitemid 34013883)
64. Garcia-Diaz, M.; Murray, M. S.; Kunkel, T. A.; Chou, K. M., Interaction between DNA Polymerase lambda and anticancer nucleoside analogs. J Biol Chem 2010, 285 (22), 16874-9.
65. Ruiz van Haperen, V. W.; Veerman, G.; Vermorken, J. B.; Peters, G. J., 2′,2′- Difluoro-deoxycytidine (gemcitabine) incorporation into RNA and DNA of tumour cell lines. Biochem Pharmacol 1993, 46 (4), 762-6. (Pubitemid 23262974)
66. Heinemann, V.; Xu, Y. Z.; Chubb, S.; Sen, A.; Hertel, L. W.; Grindey, G. B.; Plunkett, W., Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2′,2′-difluorodeoxycytidine. Mol Pharmacol 1990, 38 (4), 567-72. (Pubitemid 20356209)
67. Stubbe, J., Ribonucleotide reductases: amazing and confusing. J Biol Chem 1990, 265 (10), 5329-32.
68. Stubbe, J., Ribonucleotide reductases. Adv Enzymol Relat Areas Mol Biol 1990, 63, 349-419.
69. Pereira, S.; Cerqueira, N. M.; Fernandes, P. A.; Ramos, M. J., Computational studies on class I ribonucleotide reductase: understanding the mechanisms of action and inhibition of a cornerstone enzyme for the treatment of cancer. Eur Biophys J 2006, 35 (2), 125-35. (Pubitemid 43042771)
70. Cerqueira, N. M.; Pereira, S.; Fernandes, P. A.; Ramos, M. J., Overview of ribonucleotide reductase inhibitors: an appealing target in anti-tumour therapy. Curr Med Chem 2005, 12 (11), 1283-94.
71. Cerqueira, N. M.; Fernandes, P. A.; Ramos, M. J., Ribonucleotide reductase: a critical enzyme for cancer chemotherapy and antiviral agents. Recent Pat Anticancer Drug Discov 2007, 2 (1), 11-29.
72. Perez, M. A.; Cerqueira, N. M.; Fernandes, P. A.; Ramos, M. J., Ribonucleotide reductase: a mechanistic portrait of substrate analogues inhibitors. Curr Med Chem 2010, 17 (26), 2854-72.
73. Cerqueira, N. M.; Fernandes, P. A.; Ramos, M. J., Understanding ribonucleotide reductase inactivation by gemcitabine. Chemistry 2007, 13 (30), 8507-15. (Pubitemid 47608884)
74. Pereira, S.; Fernandes, P. A.; Ramos, M. J., Mechanism for ribonucleotide reductase inactivation by the anticancer drug gemcitabine. J Comput Chem 2004, 25 (10), 1286-94.
75. Cerqueira, N. M.; Fernandes, P. A.; Eriksson, L. A.; Ramos, M. J., Ribonucleotide activation by enzyme ribonucleotide reductase: understanding the role of the enzyme. J Comput Chem 2004, 25 (16), 2031-7.
76. Cerqueira, N. M.; Fernandes, P. A.; Eriksson, L. A.; Ramos, M. J., Dehydration of ribonucleotides catalyzed by ribonucleotide reductase: the role of the enzyme. Biophys J 2006, 90 (6), 2109-19.
77. Cerqueira, N. M.; Fernandes, P. A.; Ramos, M. J., Enzyme ribonucleotide reductase: unraveling an enigmatic paradigm of enzyme inhibition by furanone derivatives. J Phys Chem B 2006, 110 (42), 21272-81. (Pubitemid 44797402)
78. Cerqueira, N.; Femandes, P. A.; Eriksson, L. A.; Ramos, M. J., New insights into a critical biological control step of the mechanism of Ribonucleotide reductase. Theochem-J. Mol. Struct. 2004, 709 (1-3), 53-65. (Pubitemid 40037374)
79. Ramos, M. J.; Fernandes, P. A., Computational enzymatic catalysis. Accounts of chemical research 2008, 41 (6), 689-698.
80. Datta, N. S.; Shewach, D. S.; Hurley, M. C.; Mitchell, B. S.; Fox, I. H., Human T-lymphoblast deoxycytidine kinase: purification and properties. Biochemistry 1989, 28 (1), 114-23. (Pubitemid 19046729)
81. Dumontet, C.; Fabianowska-Majewska, K.; Mantincic, D.; Callet Bauchu, E.; Tigaud, I.; Gandhi, V.; Lepoivre, M.; Peters, G. J.; Rolland, M. O.; Wyczechowska, D.; Fang, X.; Gazzo, S.; Voorn, D. A.; Vanier-Viornery, A.; MacKey, J., Common resistance mechanisms to deoxynucleoside analogues in variants of the human erythroleukaemic line K562. Br J Haematol 1999, 106 (1), 78-85.
82. Heinemann, V.; Schulz, L.; Issels, R. D.; Plunkett, W. In Gemcitabine: a modulator of intracellular nucleotide and deoxynucleotide metabolism, 1995; p 11.
83. van Moorsel, C. J.; Bergman, A. M.; Veerman, G.; Voorn, D. A.; Ruiz van Haperen, V. W.; Kroep, J. R.; Pinedo, H. M.; Peters, G. J., Differential effects of gemcitabine on ribonucleotide pools of twenty-one solid tumour and leukaemia cell lines. Biochim Biophys Acta 2000, 1474 (1), 5-12. (Pubitemid 30103526)
84. Xu, Y. Z.; Plunkett, W., Modulation of deoxycytidylate deaminase in intact human leukemia cells. Action of 2',2'-difluorodeoxycytidine. Biochem Pharmacol 1992, 44 (9), 1819-27.
85. Plunkett, W.; Huang, P.; Gandhi, V., Gemcitabine: actions and interactions. Nucleosides & nucleotides 1997, 16 (7-9), 1261-1270. (Pubitemid 27494460)
86. Peters, G. J.; van der Wilt, C. L.; van Triest, B.; Codacci-Pisanelli, G.; Johnston, P. G.; van Groeningen, C. J.; Pinedo, H. M., Thymidylate synthase and drug resistance. Eur J Cancer 1995, 31A (7-8), 1299-305.
87. Huang, P.; Plunkett, W. In Induction of apoptosis by gemcitabine, 1995; p 19.
88. Ostruszka, L. J.; Shewach, D. S., The role of DNA synthesis inhibition in the cytotoxicity of 2', 2'-difluoro-2'-deoxycytidine. Cancer Chemotherapy and Pharmacology 2003, 52 (4), 325-332. (Pubitemid 37352599)
89. Miura, S.; Izuta, S., DNA polymerases as targets of anticancer nucleosides. Current Drug Targets 2004, 5 (2), 191-195. (Pubitemid 38279417)
90. Pace, E.; Melis, M.; Siena, L.; Bucchieri, F.; Vignola, A.; Profita, M.; Gjomarkaj, M.; Bonsignore, G., Effects of gemcitabine on cell proliferation and apoptosis in non-small-cell lung cancer (NSCLC) cell lines. Cancer Chemotherapy and Pharmacology 2000, 46 (6), 467-476.
91. Ferreira, C. G.; Span, S. W.; Peters, G. J.; Kruyt, F. A. E.; Giaccone, G., Chemotherapy triggers apoptosis in a caspase-8-dependent and mitochondria-controlled manner in the non-small cell lung cancer cell line NCI-H460. Cancer Research 2000, 60 (24), 7133.
92. Habiro, A.; Tanno, S.; Koizumi, K.; Izawa, T.; Nakano, Y.; Osanai, M.; Mizukami, Y.; Okumura, T.; Kohgo, Y., Involvement of p38 mitogenactivated protein kinase in gemcitabine-induced apoptosis in human pancreatic cancer cells*1. Biochemical and Biophysical Research Communications 2004, 316 (1), 71-77. (Pubitemid 38299130)
93. Abratt, R. P.; Bezwoda, W. R.; Goedhals, L.; Hacking, D. J., Weekly gemcitabine with monthly cisplatin: effective chemotherapy for advanced non-small-cell lung cancer. J Clin Oncol 1997, 15 (2), 744-9. (Pubitemid 27074244)
94. Heinemann, V., Gemcitabine plus cisplatin for the treatment of metastatic breast cancer. Clin Breast Cancer 2002, 3 Suppl 1, 24-9.
95. Heinemann, V.; Wilke, H.; Mergenthaler, H. G.; Clemens, M.; Konig, H.; Illiger, H. J.; Arning, M.; Schalhorn, A.; Possinger, K.; Fink, U., Gemcitabine and cisplatin in the treatment of advanced or metastatic pancreatic cancer. Ann Oncol 2000, 11 (11), 1399-403.
96. Eastman, A., The formation, isolation and characterization of DNA adducts produced by anticancer platinum complexes. Pharmacol Ther 1987, 34 (2), 155-66. (Pubitemid 17149009)
97. Bergman, A. M.; Ruiz van Haperen, V. W.; Veerman, G.; Kuiper, C. M.; Peters, G. J., Synergistic interaction between cisplatin and gemcitabine in vitro. Clin Cancer Res 1996, 2 (3), 521-30. (Pubitemid 26099172)
98. Pfisterer, J.; Vergote, I.; Du Bois, A.; Eisenhauer, E., Combination therapy with gemcitabine and carboplatin in recurrent ovarian cancer. Int J Gynecol Cancer 2005, 15 Suppl 1, 36-41. (Pubitemid 40696476)
99. Miller, B. E.; Blessing, J. A.; Stehman, F. B.; Shahin, M. S.; Yamada, S. D.; Secord, A. A.; Warshal, D. P.; Abulafia, O.; Richards, W. E.; Van Le, L., A phase II evaluation of weekly gemcitabine and docetaxel for second-line treatment of recurrent carcinosarcoma of the uterus: a gynecologic oncology group study. Gynecol Oncol 2010, 118 (2), 139-44.
100. Lee, E. M.; Rha, S. Y.; Lee, J.; Park, K. H.; Ahn, J. H., Phase II study of weekly docetaxel and fixed dose rate gemcitabine in patients with previously treated advanced soft tissue and bone sarcoma. Cancer Chemother Pharmacol 2011.
101. Maki, R. G.; Wathen, J. K.; Patel, S. R.; Priebat, D. A.; Okuno, S. H.; Samuels, B.; Fanucchi, M.; Harmon, D. C.; Schuetze, S. M.; Reinke, D.; Thall, P. F.; Benjamin, R. S.; Baker, L. H.; Hensley, M. L., Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]. J Clin Oncol 2007, 25 (19), 2755-63. (Pubitemid 47123184)
102. Garcia, P.; Braguer, D.; Carles, G.; el Khyari, S.; Barra, Y.; de Ines, C.; Barasoain, I.; Briand, C., Comparative effects of taxol and Taxotere on two different human carcinoma cell lines. Cancer Chemother Pharmacol 1994, 34 (4), 335-43. (Pubitemid 24216540)
103. Lavelle, F.; Bissery, M. C.; Combeau, C.; Riou, J. F.; Vrignaud, P.; Andre, S., Preclinical evaluation of docetaxel (Taxotere). Semin Oncol 1995, 22 (2 Suppl 4), 3-16.
104. Kroep, J. R.; Giaccone, G.; Tolis, C.; Voorn, D. A.; Loves, W. J.; Groeningen, C. J.; Pinedo, H. M.; Peters, G. J., Sequence dependent effect of paclitaxel on gemcitabine metabolism in relation to cell cycle and cytotoxicity in non-small-cell lung cancer cell lines. Br J Cancer 2000, 83 (8), 1069-76.
105. Bernhard, J.; Dietrich, D.; Scheithauer, W.; Gerber, D.; Bodoky, G.; Ruhstaller, T.; Glimelius, B.; Bajetta, E.; Schuller, J.; Saletti, P.; Bauer, J.; Figer, A.; Pestalozzi, B. C.; Kohne, C. H.; Mingrone, W.; Stemmer, S. M.; Tamas, K.; Kornek, G. V.; Koeberle, D.; Herrmann, R., Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol 2008, 26 (22), 3695-701.
106. Miyanishi, K.; Ishiwatari, H.; Hayashi, T.; Takahashi, M.; Kawano, Y.; Takada, K.; Ihara, H.; Okuda, T.; Takanashi, K.; Takahashi, S., A Phase I trial of arterial infusion chemotherapy with gemcitabine and 5-fluorouracil for unresectable advanced pancreatic cancer after vascular supply distribution via superselective embolization. Japanese journal of clinical oncology 2008, 38 (4), 268.
107. Pallis, A. G.; Agelidou, A.; Agelaki, S.; Varthalitis, I.; Pavlakou, G.; Gerogianni, A.; Papakotoulas, P.; Rapti, A.; Chandrinos, V.; Christophyllakis, C., A multicenter randomized phase II study of the irinotecan/gemcitabine doublet versus irinotecan monotherapy in previously treated patients with extensive stage small-cell lung cancer. Lung Cancer 2009, 65 (2), 187-191.
108. Moore, M. J.; Goldstein, D.; Hamm, J.; Figer, A.; Hecht, J. R.; Gallinger, S.; Au, H. J.; Murawa, P.; Walde, D.; Wolff, R. A.; Campos, D.; Lim, R.; Ding, K.; Clark, G.; Voskoglou-Nomikos, T.; Ptasynski, M.; Parulekar, W., Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007, 25 (15), 1960-6. (Pubitemid 46972777)