Selective cytokine inhibitory drugs with enhanced antiangiogenic activity control tumor growth through vascular inhibition.
Selective cytokine inhibitory drugs (SelCIDs) are a novel class of phosphodiesterase 4 inhibitors discovered during a thalidomide analog discovery program. These analogs were evaluated for their ability to inhibit tumor angiogenesis, vascularity, and growth. Two analogs (CC-7034 and CC-9088) were identified that had enhanced antiangiogenic activity in Matrigel assays compared with parental thalidomide. These analogs also inhibited the growth of established K1735 and RENCA murine tumors. Tumors whose growth was suppressed by SelCID treatment exhibited decreased vessel density together with increased tumor cell hypoxia and death. The decrease in vascularity produced by SelCID treatment is attributed to a selective loss of vessels devoid of pericyte coverage, suggesting that these agents target immature tumor vessels. That tumor cell death was localized to relatively avascular or hypoxic areas, coupled with the fact that none of the analogs was cytotoxic in vitro against the tumor cells, demonstrates that these analogs are novel antivascular agents with potent antitumor activity.
Gee
Michael S
MS
Department of Medicine and the Cancer Center, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA.
Makonnen
Sosina
S
al-Kofahi
Khalid
K
Roysam
Badri
B
Payvandi
Faribourz
F
Man
Hon-Wah
HW
Muller
George W
GW
Lee
William M F
WM
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004730:Endothelium, Vascular / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D016207:Cytokines; D013792:Thalidomide