| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Departments of Medical Oncology [R. G., J. A., W. P] and Hematology [H. K., M. J. K.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Lilly Research Laboratories [P. T.], Indianapolis, Indiana 46285
The objective of this study was to determine the dose rate of 2',2'-difluorodeoxycytidine (dFdC) that maximizes the accumulation of the active 5'-triphosphate (dFdCTP) in circulating leukemia cells during therapy. The investigational approach was to evaluate the relationship between plasma dFdC and the accumulation of dFdCTP by circulating leukemia cells during infusion of different dFdC dose rates in the same individuals. Four patients with relapsed leukemia were treated weekly with two or three consecutive infusions of 800 mg/m2, the first administered over 1 h, the second over 2 h, and the third over 3 h. Two patients, one with acute myelogenous leukemia and one with acute lymphocytic leukemia, received all three infusions, but thrombocytopenia prohibited infusion of the third dose to two patients with chronic lymphocytic leukemia. The average steady-state plasma dFdC levels, achieved within 15 min after the infusion began, were 43.8 µM during infusion of 800 mg/m2/h, 9.4 µM during infusion of 400 mg/m2/h, and 5.6 µM at 267 mg/m2/h. The median area under the concentration times time curve of dFdCTP in leukemia cells during infusion was increased 2.3- and 5.1-fold for the 2- and 3-h infusions, respectively. In vitro incubations of leukemia cells from the four patients with 2.5–100 µM dFdC for 1 h showed that the maximum cellular accumulation of dFdCTP was produced by 15–20 µM dFdC. We conclude that a dose rate of >400 mg/m2/h was required to achieve plasma dFdC levels that supported the maximum rate of dFdCTP accumulation in leukemia cells.
1 This work was supported in part by grant CA32839 from the National Cancer Institute, Department of Health and Human Services, and grant CH-130 from the American Cancer Society.
2 To whom requests for reprints should be addressed, at Department of Medical Oncology, Box 52, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.
Received 4/18/90. Accepted 7/30/90.
This article has been cited by other articles:
|
|
 |
|
  B. R. Tan, W. S. Brenner, J. Picus, S. Marsh, F. Gao, C. Fournier, P. M. Fracasso, J. James, J. L. Yen-Revollo, and H. L. Mcleod Phase I study of biweekly oxaliplatin, gemcitabine and capecitabine in patients with advanced upper gastrointestinal malignancies Ann. Onc., October 1, 2008; 19(10): 1742 - 1748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L.-S. Tham, L. Wang, R. A. Soo, S.-C. Lee, H.-S. Lee, W.-P. Yong, B.-C. Goh, and N. H.G. Holford A Pharmacodynamic Model for the Time Course of Tumor Shrinkage by Gemcitabine + Carboplatin in Non-Small Cell Lung Cancer Patients Clin. Cancer Res., July 1, 2008; 14(13): 4213 - 4218. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. H. Reddy, P.-E. Marque, C. Dubernet, S.-L. Mouelhi, D. Desmaele, and P. Couvreur Preclinical Toxicology (Subacute and Acute) and Efficacy of a New Squalenoyl Gemcitabine Anticancer Nanomedicine J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 484 - 490. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Nieto, M. L. Grossbard, and P. Kozuch Metastatic Pancreatic Cancer 2008: Is the Glass Less Empty? Oncologist, May 1, 2008; 13(5): 562 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Veltkamp, J. H. Beijnen, and J. H.M. Schellens Prolonged Versus Standard Gemcitabine Infusion: Translation of Molecular Pharmacology to New Treatment Strategy Oncologist, March 1, 2008; 13(3): 261 - 276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Gandhi Questions About Gemcitabine Dose Rate: Answered or Unanswered? J. Clin. Oncol., December 20, 2007; 25(36): 5691 - 5694. [Full Text] [PDF]
|
|
|
|
|
|
T El Gnaoui, J Dupuis, K Belhadj, J-P Jais, A Rahmouni, C Copie-Bergman, I Gaillard, M Divine, I Tabah-Fisch, F Reyes, et al. Rituximab, gemcitabine and oxaliplatin: an effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy Ann. Onc., August 1, 2007; 18(8): 1363 - 1368. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D Santini, V Virzi, B Vincenzi, L Rocci, V Leoni, and G Tonini A phase I trial of fixed dose rate gemcitabine plus capecitabine in metastatic cancer patients Ann. Onc., March 1, 2007; 18(3): 576 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Soo, L. Z. Wang, L. S. Tham, W. P. Yong, M. Boyer, H. L. Lim, H. S. Lee, M. Millward, S. Liang, P. Beale, et al. A multicentre randomised phase II study of carboplatin in combination with gemcitabine at standard rate or fixed dose rate infusion in patients with advanced stage non-small-cell lung cancer Ann. Onc., July 1, 2006; 17(7): 1128 - 1133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. P. Lee, M. J.A. de Jonge, A. E. O'Donnell, K. L. Schothorst, J. Hanwell, J. B. Chick, R. A. Brooimans, L. M. Adams, D. W. Drolet, J. S. de Bono, et al. A Phase I Study of a New Nucleoside Analogue, OSI-7836, Using Two Administration Schedules in Patients with Advanced Solid Malignancies. Clin. Cancer Res., May 1, 2006; 12(9): 2841 - 2848. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. H. Ko, E. Dito, B. Schillinger, A. P. Venook, E. K. Bergsland, and M. A. Tempero Phase II Study of Fixed Dose Rate Gemcitabine With Cisplatin for Metastatic Adenocarcinoma of the Pancreas J. Clin. Oncol., January 20, 2006; 24(3): 379 - 385. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. S. P. Rocha Lima and A. M. Flores Gemcitabine Doublets in Advanced Pancreatic Cancer: Should We Move On? J. Clin. Oncol., January 20, 2006; 24(3): 327 - 329. [Full Text] [PDF]
|
|
|
|
|
|
P. M. Anderson, G. A. Wiseman, L. Erlandson, V. Rodriguez, B. Trotz, S. A. Dubansky, and K. Albritton Gemcitabine Radiosensitization after High-Dose Samarium for Osteoblastic Osteosarcoma Clin. Cancer Res., October 1, 2005; 11(19): 6895 - 6900. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Pauwels, A. E.C. Korst, F. Lardon, and J. B. Vermorken Combined Modality Therapy of Gemcitabine and Radiation Oncologist, January 1, 2005; 10(1): 34 - 51. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Reid, W. Qu, S. L. Safgren, M. M. Ames, M. D. Krailo, N. L. Seibel, J. Kuttesch, and J. Holcenberg Phase I Trial and Pharmacokinetics of Gemcitabine in Children With Advanced Solid Tumors J. Clin. Oncol., June 15, 2004; 22(12): 2445 - 2451. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Leu, L. J. Ostruszka, D. Shewach, M. Zalupski, V. Sondak, J. S. Biermann, J. S.-J. Lee, C. Couwlier, K. Palazzolo, and L. H. Baker Laboratory and Clinical Evidence of Synergistic Cytotoxicity of Sequential Treament With Gemcitabine Followed by Docetaxel in the Treatment of Sarcoma J. Clin. Oncol., May 1, 2004; 22(9): 1706 - 1712. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Duxbury, H. Ito, M. J. Zinner, S. W. Ashley, and E. E. Whang Inhibition of Src Tyrosine Kinase Impairs Inherent and Acquired Gemcitabine Resistance in Human Pancreatic Adenocarcinoma Cells Clin. Cancer Res., April 1, 2004; 10(7): 2307 - 2318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Garcia-Manteiga, M. Molina-Arcas, F. J. Casado, A. Mazo, and M. Pastor-Anglada Nucleoside Transporter Profiles in Human Pancreatic Cancer Cells: Role of hCNT1 in 2',2'-Difluorodeoxycytidine- Induced Cytotoxicity Clin. Cancer Res., October 15, 2003; 9(13): 5000 - 5008. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. S. Shewach and T. S. Lawrence It's What's Inside That Counts J. Clin. Oncol., September 15, 2003; 21(18): 3383 - 3384. [Full Text] [PDF]
|
|
|
|
|
|
M. Tempero, W. Plunkett, V. Ruiz van Haperen, J. Hainsworth, H. Hochster, R. Lenzi, and J. Abbruzzese Randomized Phase II Comparison of Dose-Intense Gemcitabine: Thirty-Minute Infusion and Fixed Dose Rate Infusion in Patients With Pancreatic Adenocarcinoma J. Clin. Oncol., September 15, 2003; 21(18): 3402 - 3408. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Rizzieri, V. K. Ibom, J. O. Moore, C. M. DeCastro, G. L. Rosner, D. J. Adams, T. Foster, N. Payne, M. Thompson, J. J. Vredenburgh, et al. Phase I Evaluation of Prolonged-infusion Gemcitabine with Fludarabine for Relapsed or Refractory Acute Myelogenous Leukemia Clin. Cancer Res., February 1, 2003; 9(2): 663 - 668. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Fracasso, J. S. Rader, R. Govindan, T. J. Herzog, M. A. Arquette, A. Denes, D. G. Mutch, J. Picus, B. R. Tan, C. L. Fears, et al. Phase I study of rubitecan and gemcitabine in patients with advanced malignancies Ann. Onc., November 1, 2002; 13(11): 1819 - 1825. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Nabhan, D. Gajria, N. L. Krett, V. Gandhi, K. Ghias, and S. T. Rosen Caspase Activation Is Required for Gemcitabine Activity in Multiple Myeloma Cell Lines Mol. Cancer Ther., November 1, 2002; 1(13): 1221 - 1227. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Hensley, R. Maki, E. Venkatraman, G. Geller, M. Lovegren, C. Aghajanian, P. Sabbatini, W. Tong, R. Barakat, and D. R. Spriggs Gemcitabine and Docetaxel in Patients With Unresectable Leiomyosarcoma: Results of a Phase II Trial J. Clin. Oncol., June 15, 2002; 20(12): 2824 - 2831. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Gandhi, W. Plunkett, M. Du, M. Ayres, and E. H. Estey Prolonged Infusion of Gemcitabine: Clinical and Pharmacodynamic Studies During a Phase I Trial in Relapsed Acute Myelogenous Leukemia J. Clin. Oncol., February 1, 2002; 20(3): 665 - 673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Rizzieri, A. J. Bass, G. L. Rosner, J. P. Gockerman, C. M. DeCastro, W. P. Petros, D. J. Adams, M. J. Laughlin, P. Davis, T. Foster, et al. Phase I Evaluation of Prolonged-Infusion Gemcitabine With Mitoxantrone for Relapsed or Refractory Acute Leukemia J. Clin. Oncol., February 1, 2002; 20(3): 674 - 679. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.-Y. Yang, L. Li, H. Jiang, Y. Shen, and W. Plunkett Expression of ERCC1 Antisense RNA Abrogates Gemcitabine-mediated Cytotoxic Synergism with Cisplatin in Human Colon Tumor Cells Defective in Mismatch Repair but Proficient in Nucleotide Excision Repair Clin. Cancer Res., March 1, 2000; 6(3): 773 - 781. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. R. Mackey, S. Y. M. Yao, K. M. Smith, E. Karpinski, S. A. Baldwin, C. E. Cass, and J. D. Young Gemcitabine Transport in Xenopus Oocytes Expressing Recombinant Plasma Membrane Mammalian Nucleoside Transporters J Natl Cancer Inst, November 3, 1999; 91(21): 1876 - 1881. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J Gruber, F Geisen, R Sgonc, A Egle, A Villunger, G Boeck, G Konwalinka, and R Greil 2',2'-Difluorodeoxycytidine (gemcitabine) induces apoptosis in myeloma cell lines resistant to steroids and 2-chlorodeoxyadenosine (2-CdA) Stem Cells, May 1, 1996; 14(3): 351 - 362. [Abstract]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
