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Conrad Notes
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J. Folkman, MD, Children's Hospital, Boston, Mass, foresees preventing chemotherapy resistance by pretreatment with angiogenesis inhibitors. Solid tumors and possibly acute lymphoblastic leukemia (ALL) in children are angiogenesis-dependent. Preclinical studies with naturally occurring inhibitors such as angiostatin, endostatin, and vasculostatin support evaluation in cancer patients.

Tumor and microvascular endothelial cells According to Folkman, virtually all tumors and their metastases have these interdependent cells. Both drive and support each other by specific growth and survival factors. One endothelial cell may support as many as 50 human tumor cells.

Angiogenesis appears to start when primary tumor cells, microscopic in size, undergo phenotypic change to become potentially lethal. Now, the tumor mass can expand and shed cells into the circulation.

Angiostatin, endostatin and vasculostatin The Children's Hospital group is investigating three potent proteins which inhibit angiogenesis. All are internal fragments of larger proteins: (1) angiostatin from plasminogen, (2) endostatin from collagen XVIII found in the basement membrane of blood vessel walls, and (3) vasculostatin from a carrier protein of thyroid hormone and retinol.

Boehm and coworkers used endostatin in mice bearing Lewis lung carcinoma, fibrosarcoma, or melanoma (Nature 1997;390:404-407). Tumor regression signalled stopping treatment; regrowth prompted resuming endostatin injections. No tumor regrowth could be seen after 6, 4, and 2 treatment cycles according to tumor type. Drug-resistance did not develop with repeated endostatin injections.

Leukemia and angiogenesis Does the solid tumor model apply to leukemia? According to Brunner et al, bone marrow cells produce basic fibroblast growth factor (Blood 1993;81:631-638). Endothelial cells also drive leukemia cells via granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF). Other data support the dependency of leukemia on angiogenesis.

Patients with ALL produce high urinary levels of a biologically active angiogenic stimulant, basic fibroblast growth factor (bFGF), to suggest that leukemia may be angiogenic. The study on 40 ALL children by Atayde and coworkers showed intensely neovascular bone marrow (Am J Pathol 1997;150:815-821). Therefore, in Folkman's opinion, leukemia may be angiogenesis-dependent.

Presenter discussion Endothelial cells closely control tumor growth, invasiveness, metastasis, progression, dormancy, and apoptosis. Since solid tumors and possibly leukemia are angiogenesis-dependent, one strategy for preventing resistance to chemotherapy is the use of antiangiogenic agents. Perhaps this class of drugs will serve as a platform for treating cancer in combination with other preparations such as immunologic, genetic, telomerase inhibitors, apoptotics, etc.
Conrad comments The 1971 seminar of Folkman ended by concluding that tumor and endothelial cells constitute an interdependent ecosystem (N Engl J Med 1971;285:1182-1186). Folkman speculated that blocking angiogenesis may be useful in treating cancer. An update on the 1971 report, including studies of other investigators, appears in Cancer Medicine (4th ed. Baltimore:Williams & Wilkins;1997;1:181-204). Also, this issue of Conrad Notes includes the related report of Kakkar.

Eugene A. Conrad

Presented at The American Society of Hematology (ASH) Meeting, December 5-9, 1997
Copyright © 1998 Conrad Group, Inc. All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078-2230 / February 1998
Send comments to: ConradNote@aol.com

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