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 id...

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Bibliographic Details
Published inCancer research (Chicago, Ill.) Vol. 63; no. 23; pp. 8073 - 8078
Main Authors GEE, Michael S, MAKONNEN, Sosina, AL-KOFAHI, Khalid, ROYSAM, Badri, PAYVANDI, Faribourz, MAN, Hon-Wah, MULLER, George W, LEE, William M. F
Format Journal Article
LanguageEnglish
Published Philadelphia, PA American Association for Cancer Research 01.12.2003
Subjects
Angiogenesis Inhibitors - pharmacology
Animals
Antineoplastic agents
Biological and medical sciences
Cell Division - drug effects
Cell Hypoxia - physiology
Cytokines - antagonists & inhibitors
Endothelium, Vascular - drug effects
Medical sciences
Mice
Mice, Inbred BALB C
Mice, Inbred C3H
Neoplasms, Experimental - blood supply
Neoplasms, Experimental - drug therapy
Neoplasms, Experimental - pathology
Neovascularization, Pathologic - drug therapy
Pharmacology. Drug treatments
Thalidomide - analogs & derivatives
Thalidomide - pharmacology
Tumors
Drug
Regulation(control)
Inhibitor
Malignant tumor
Tumor growth
Cytokine
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Summary: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.
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ISSN:0008-5472
1538-7445