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Flavopiridol Induces Apoptosis of Normal Lymphoid Cells, Causes
Immunosuppression, and Has Potent Antitumor Activity In Vivo
Against Human Leukemia and Lymphoma Xenografts
Francisco Arguello,
Mark Alexander,
Judith A. Sterry,
Gabriela Tudor,
Erik M. Smith,
Naina T. Kalavar,
John F. Greene Jr,
William Koss,
C. David Morgan,
Sherman F. Stinson,
Timothy J. Siford,
W.
Gregory Alvord,
Richard L. Klabansky, and
Edward A. Sausville
From the Laboratory of Drug Discovery Research and Development,
Developmental Therapeutics Program Division of Cancer Treatment and
Diagnosis, the Science Application International Corporation, and Data
Management Services, Inc, National Cancer Institute-Frederick Cancer
Research and Development Center, Frederick, MD; the Division of
Clinical Laboratories, University of Rochester Strong Memorial
Hospital, Rochester, NY; and the Department of Pathology and Immunology
Section, Scott & White Clinic, Temple, TX.
Flavopiridol is a novel semisynthetic flavone derivative of the
alkaloid rohitukine. Flavopiridol is known to inhibit potently the
activity of multiple cyclin-dependent kinases. We have assessed its
effects on normal and malignant cells in preclinical animal models of
localized and disseminated human hematopoietic neoplasms. Flavopiridol,
when administered as daily bolus intravenous (IV) injections, produced
selective apoptosis of cells in the thymus, spleen, and lymph nodes,
resulting in atrophy of these organs. With the exception of the
intestinal crypts, apoptosis or tissue damage was absent in all other
organs investigated (kidneys, liver, lungs, bone/bone marrow, muscle,
and heart). Flavopiridol had a marked apoptotic effect documented by
DNA nick-end labeling, or DNA agarose gels in xenografts of human
hematopoietic tumors HL-60, SUDHL-4, and Nalm/6. After treatment with
7.5 mg/kg flavopiridol bolus IV or intraperitoneal on each of 5 consecutive days, 11 out of 12 advanced stage subcutaneous (s.c.) human
HL-60 xenografts underwent complete regressions, and animals remained
disease-free several months after one course of flavopiridol treatment.
SUDHL-4 s.c. lymphomas treated with flavopiridol at 7.5 mg/kg bolus IV for 5 days underwent either major (two out of eight mice) or complete (four out of eight mice) regression, with two animals remaining disease-free for more than 60 days. The overall growth delay was 73.2%. The acquired immunodeficiency syndrome-associated lymphoma AS283 showed no significant response when flavopiridol was used in
advanced s.c. tumors, but when treatment was initiated in early stages,
there was a complete regression of the early tumors, and a significant
overall growth delay (>84%). When flavopiridol was used in severe
combined immunodeficient mice bearing disseminated human acute
lymphoblastic leukemia Nalm/6 cells, there was 15-day prolongation in
survival (P = .0089). We conclude that flavopiridol greatly
influences apoptosis in both normal and malignant hematopoietic tissues. This activity was manifested in our study as a potent antileukemia or antilymphoma effect in human tumor xenografts, which
was dose and schedule dependent. These findings provide compelling
evidence for the use of flavopiridol in human hematologic malignancies.
Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2482-2490
© 1998 by The American Society of Hematology.
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