Endothelial cell effects of cytotoxics: balance between desired and unwanted effects.
Since Folkman defined angiogenesis more than 25 years ago as the most important process in tumour growth and metastasis, specific anti-angiogenic agents have been developed. One obvious route to block this process was until recently overlooked, however. Tumour endothelial cells are different from normal endothelial cells and may respond differently to conventional cytotoxics. Chemotherapeutic-induced vascular toxicity has been observed in various clinical studies and seems to be based on endothelial cell damage as seen in vitro in human umbilical vein endothelial cells (HUVEC) models with protracted low-dose cytostatic exposure. Translated into the clinical setting, such "metronomically" administered chemotherapy could lead to anti-angiogenesis enhancing anti-tumour efficacy of cytostatic drugs. This paper reviews the desired anti-tumour endothelial activity versus the unwanted general vascular toxicity of cytostatic drugs. Several ways to enhance the anti-tumour activity and to circumvent the unwanted vascular toxicity of these "accidental" anti-angiogenic drugs will be discussed.
de Vos
F Y F L
FY
Department Internal Medicine, Division Medical Oncology, University Hospital Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
Willemse
P H B
PH
de Vries
E G E
EG
Gietema
J A
JA
D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic