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[Cancer Research 57, 3375-3380, August 15, 1997]
© 1997 American Association for Cancer Research
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Cytotoxic Synergy between Flavopiridol (NSC 649890, L86-8275) and Various Antineoplastic Agents: The Importance of Sequence of Administration1

Keith C. Bible2 and Scott H. Kaufmann

Division of Oncology Research, Mayo Clinic, and Department of Pharmacology, Mayo Medical School, Rochester, Minnesota 55905

Flavopiridol, the first potent cyclin-dependent kinase inhibitor to undergo clinical trials as an antineoplastic agent in the United States, has attracted considerable attention because of its unique cellular targets and its ability to kill noncycling tumor cells in vitro. To better understand how flavopiridol might be used clinically, the present study used colony-forming assays to examine the cytotoxicity resulting from combining flavopiridol with eight other antineoplastic agents in four different administration schedules in A549 human non-small cell lung carcinoma cells in vitro. Cytotoxic synergy, as assessed by the median effect method, resulted when flavopiridol was combined with seven of the eight tested antineoplastic agents but was highly dependent upon administration schedule. Cisplatin was the only agent that resulted in sequence-independent synergy when combined with flavopiridol. For paclitaxel, cytarabine, topotecan, doxorubicin, and etoposide, synergy was more pronounced when the agents were administered before flavopiridol rather than concomitant with or following flavopiridol. Examination suggested that this sequence dependence reflected arrest of cells in G1 and G2 phases of the cell cycle during and for 24 h following flavopiridol treatment. Interestingly, 48–72 h after flavopiridol removal, the fraction of surviving cells in S phase increased 2–3-fold relative to untreated controls. Consistent with these results, administration of flavopiridol for 24 h followed 3 days later by exposure to an S phase-active agent (cytarabine or 5-fluorouracil) resulted in a highly synergistic interaction. These results highlight the importance of administration schedule when combining flavopiridol with other agents and provide a starting point for examining the effect of flavopiridol in drug combinations in vivo.

1 Supported in part by U01 CA69912 and a grant from the Jack Taylor Family Foundation. S. H. K. is a Leukemia Society Scholar.

2 To whom requests for reprints should be addressed, at Guggenheim 1301. Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Phone: (507) 284-8950; Fax: (507) 284-3906.

Received 5/14/97. Accepted 7/ 2/97.




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Rational Approaches to Design of Therapeutics Targeting Molecular Markers
Hematology, January 1, 2001; 2001(1): 443 - 462.
[Abstract] [Full Text] [PDF]

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 Antimicrob. Agents Chemother.Home page
T. V. Achenbach, E. P. Slater, H. Brummerhop, T. Bach, and R. Müller
Inhibition of Cyclin-Dependent Kinase Activity and Induction of Apoptosis by Preussin in Human Tumor Cells
Antimicrob. Agents Chemother., October 1, 2000; 44(10): 2794 - 2801.
[Abstract] [Full Text]

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 Clin. Cancer Res.Home page
F. Innocenti, W. M. Stadler, L. Iyer, J. Ramírez, E. E. Vokes, and M. J. Ratain
Flavopiridol Metabolism in Cancer Patients Is Associated with the Occurrence of Diarrhea
Clin. Cancer Res., September 1, 2000; 6(9): 3400 - 3405.
[Abstract] [Full Text]

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 Clin. Cancer Res.Home page
A. A. Adjei, J. N. Davis, C. Erlichman, P. A. Svingen, and S. H. Kaufmann
Comparison of Potential Markers of Farnesyltransferase Inhibition
Clin. Cancer Res., June 1, 2000; 6(6): 2318 - 2325.
[Abstract] [Full Text]

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 Cancer Res.Home page
K. C. Bible, R. H. Bible Jr., T. J. Kottke, P. A. Svingen, K. Xu, Y.-P. Pang, E. Hajdu, and S. H. Kaufmann
Flavopiridol Binds to Duplex DNA
Cancer Res., May 1, 2000; 60(9): 2419 - 2428.
[Abstract] [Full Text]

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 JNCI J Natl Cancer InstHome page
A. M. Senderowicz and E. A. Sausville
Preclinical and Clinical Development of Cyclin-Dependent Kinase Modulators
J Natl Cancer Inst, March 1, 2000; 92(5): 376 - 387.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
M. Motwani, X.-k. Li, and G. K. Schwartz
Flavopiridol, a Cyclin-dependent Kinase Inhibitor, Prevents Spindle Inhibitor-induced Endoreduplication in Human Cancer Cells
Clin. Cancer Res., March 1, 2000; 6(3): 924 - 932.
[Abstract] [Full Text]

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 Clin. Cancer Res.Home page
K. C. Bible, S. A. Boerner, K. Kirkland, K. L. Anderl, D. Bartelt Jr., P. A. Svingen, T. J. Kottke, Y. K. Lee, S. Eckdahl, P. G. Stalboerger, et al.
Characterization of an Ovarian Carcinoma Cell Line Resistant to Cisplatin and Flavopiridol
Clin. Cancer Res., February 1, 2000; 6(2): 661 - 670.
[Abstract] [Full Text]

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 Clin. Cancer Res.Home page
T. E. Witzig, M. Timm, M. Stenson, P. A. Svingen, and S. H. Kaufmann
Induction of Apoptosis in Malignant B Cells by Phenylbutyrate or Phenylacetate in Combination with Chemotherapeutic Agents
Clin. Cancer Res., February 1, 2000; 6(2): 681 - 692.
[Abstract] [Full Text]

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 JCOHome page
W. M. Stadler, N. J. Vogelzang, R. Amato, J. Sosman, D. Taber, D. Liebowitz, and E. E. Vokes
Flavopiridol, A Novel Cyclin-Dependent Kinase Inhibitor, in Metastatic Renal Cancer: A University of Chicago Phase II Consortium Study
J. Clin. Oncol., January 14, 2000; 18(2): 371 - 371.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
Y. Li, M. Bhuiyan, S. Alhasan, A. M. Senderowicz, and F. H. Sarkar
Induction of Apoptosis and Inhibition of c-erbB-2 in Breast Cancer Cells by Flavopiridol
Clin. Cancer Res., January 1, 2000; 6(1): 223 - 229.
[Abstract] [Full Text]

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 Clin. Cancer Res.Home page
S. Ruller, C. Stahl, G. Kohler, B. Eickhoff, J. Breder, M. Schlaak, and J. van der Bosch
Sensitization of Tumor Cells to Ribotoxic Stress-induced Apoptotic Cell Death: A New Therapeutic Strategy
Clin. Cancer Res., October 1, 1999; 5(10): 2714 - 2725.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
G. I. Shapiro, D. A. Koestner, C. B. Matranga, and B. J. Rollins
Flavopiridol Induces Cell Cycle Arrest and p53-independent Apoptosis in Non-Small Cell Lung Cancer Cell Lines
Clin. Cancer Res., October 1, 1999; 5(10): 2925 - 2938.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
M. Motwani, T. M. Delohery, and G. K. Schwartz
Sequential Dependent Enhancement of Caspase Activation and Apoptosis by Flavopiridol on Paclitaxel-treated Human Gastric and Breast Cancer Cells
Clin. Cancer Res., July 1, 1999; 5(7): 1876 - 1883.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
T. J. Kottke, A. L. Blajeski, L. M. Martins, P. W. Mesner Jr., N. E. Davidson, W. C. Earnshaw, D. K. Armstrong, and S. H. Kaufmann
Comparison of Paclitaxel-, 5-Fluoro-2'-deoxyuridine-, and Epidermal Growth Factor (EGF)-induced Apoptosis. EVIDENCE FOR EGF-INDUCED ANOIKIS
J. Biol. Chem., May 28, 1999; 274(22): 15927 - 15936.
[Abstract] [Full Text] [PDF]


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