Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Differential effects of drugs on vascular channels formed by tumor cells vs vascular channels formed by endothelial cells

SM Rybak PhD, E Sanovich PhD, M Hollingshead PhD, DL Newton PhD, G Kaur BS, EA Sausville MD PhD

Angiogenesis Resource Group and Developmental Therapeutics Program, Div Cancer Treatment and Diagnosis, National Cancer Institute/Frederick Cancer Research and Development Center, Frederick, MD, USA,

AIMS: ICRF159 (Razoxane) a bisdioxopiperazine compound was previously reported to improve structurally imperfect red blood cell containing vascular channels typically lined by tumor cells. The effects of TNP470, a putative anti-angiogenic compound and ICRF159 were characterized for effects on tumor growth and vascular channels in a murine melanoma model. METHODS: After subcutaneously implanting B16F10 melanoma cells into the flanks of C57BL/6N mice double blinded ultrastructural observations were correlated with tumor growth. Drug effects were characterized on tumor cell growth in cell culture and on tumor cell phenotypic behavior when cultured on a basement membrane substrate. RESULTS: Vascular channels - existing between strands of tumor cells - contained pools of red blood cells occasionally admixed with melanin containing tumor cells. Cultured melanoma or human umbilical vein endothelial (HUVEC) cells were insensitive to ICRF159. However after 72 h in the presence TNP470 the growth of both HUVEC and melanoma cells was inhibited. Despite the lack of significant in vitro cytotoxicity ICRF159 significantly inhibited tumor growth in mice ( T/C 34 ). Though cytotoxic to both tumor and endothelial cells the T/C of TNP470 was 55. CONCLUSIONS: Morphology of tumor blood vessels was differentially impacted by the drugs. In vivo, ICRF159 differentiated tumor lined vascular channels. In vitro, ICRF159 blocked cord formation by melanoma cells while TNP470 blocked cord formation by HUVECs. These results bear on the controversial concept of vasculogenic mimicry [Fausto, N. (2000) Am. J. Pathol:156, 359] and on the necessity of devising therapeutic strategies that target all forms of vascular channels in tumors.

KEY WORDS: anti-angiogenesis.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on molecular detection & therapy.