Antiangiogenic Action of Chemically Modified Tetracyclines in Breast Cancer
Abstract
The long term objective of this project remains to evaluate nonantimicrobial chemically modified tetracyclines (CMTs) as inhibitors of the angiogenic response which maintains breast tumor growth and proliferation. In this third year, we expanded our studies on release of VEGF from breast tumor cell lines to include a fourth cell line, MDA-MB-435s, which is more invasive than MCF-7: CMT-300 stimulated release of VEGF from both cell lines except at the high dose of 50 uM, but CMT-308 inhibited release from both cell lines in a dose dependent fashion. TGF-beta augmented VEGF release by both cell lines, but this enhanced release was also inhibited by CMT-308 in a dose-dependent fashion. Neither CMT triggered cytotoxicity in either line at doses up to 50 uM. All CMT-induced diminution of released VEGF levels could be ascribed to inhibition of synthesis and/or secretion, rather than degradation of pre-existing growth factor. The steady-state levels of intracellular VEGF species (via Western blot) and mRNAs for these species (via PCR) were unaffected by TGF-beta or CMTs, suggesting primary effects on the secretory pathway. In contrast, intracellular pools of VEGF in Mono Mac 6 cells were diminished by CMT-308, although by far less than the inhibition of secretion; there was no significant effect of CMTs on the multiple VEGF mRNA species. Both CMT-300 and CMT-308 visibly reduced tube formation by human microvascular endothelial cells on collagen, although by less than when cells were plated on Matrigel. These results offer further support for our argument that CMTs may be of use as antiangiogenic agents in management of breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2004
- Accession Number
- ADA427288
Entities
People
- Sanford R. Simon
Organizations
- State University of New York