TY - JOUR
T1 - Soluble E-selectin in cancer patients as a marker of the therapeutic efficacy of CM101, a tumor-inhibiting anti-neovascularizaton agent, evaluated in phase I clinical trial
AU - Wamil, Barbara D.
AU - Thurman, Gary B.
AU - Sundell, Hakan W.
AU - DeVore, Russell F.
AU - Wakefield, Gail
AU - Johnson, David H.
AU - Wang, Yue Fen
AU - Hellerqvist, Carl G.
PY - 1997
Y1 - 1997
N2 - A polysaccharide toxin, GBS toxin, is produced by group B Streptococcus (GBS) isolates from neonates who died of 'early-onset disease'. GBS toxin, named CM101 in the clinic, was hypothesized, on the basis of our previous in vivo studies, to induce inflammation in pulmonary neovasculature in neonates by crosslinking of embryonic receptors still expressed after birth and in tumor neovasculature in adults. Immunohistochemical in vitro analysis of human biopsies showed that tumor neovasculature is indeed a binding site for CM101. In vivo studies in mice have demonstrated that CM101 induced inflammatory responses in neoplastic tumor neovasculature causing inhibition of tumor growth and tumor cell necrosis. These experimental observations warranted a phase 1 clinical trial for CM101 as an anti-neovascularization agent in human cancer therapy. Cancer patients received one cycle of therapy consisting of three treatments during 1 week. CM101 was administered over 15 min by i.v. infusion. Dosages of 7.5 μg/kg (1 U/kg), n = 3; 15 μg/kg (2 U/kg), n = 6; 24.75 μg/kg (3.3 U/kg), n = 3; and 37.5 μg/kg (5 U/kg), n = 3 were used. Enzyme-linked immunosorbent sandwich assays (ELISA) of the patients' sera showed a marked elevation of soluble E-selectin with a peak concentration observed at 8-12 h after each CM101 infusion. The average baseline value for soluble E-selectin prior to the first treatment was 97.3 ± 23.4 ng/ml (mean ± SEM, n = 15) and the average peak level at 8 h was 441.6 ± 62.4 (mean ± SEM, n = 15; P < 0.001). Subsequent treatments gave average maximum soluble E-selectin levels again at 8 h of 466.9 ± 87.6 and 412.0 ± 67.8 ng/ml, for treatments 2 and 3 respectively. Baseline values for treatments 2 and 3 were 192.3 ± 26.4 and 226.4 ± 26.1 ng/ml respectively (p < 0.01 versus treatment 1). Out of 15 patients, 5 showed tumor reduction or stabilization and were given additional cycles of therapy. CM101 induced an increase in soluble E-selectin levels, which remained elevated over baseline at the start of the following treatment cycles. The baseline remained elevated for several weeks after the final treatment, i.e., P < 0.01 for levels before treatment 1 compared to those at week 4 after treatment. Elevated soluble E-selectin is considered proof of endothelial engagement in an inflammatory process. Our data support the contention that the inflammatory response observed in these cancer patients is targeting the tumor neovasculature and that measurement of soluble E-selectin levels in patients treated with CM101 can provide important information on the magnitude of CM101-mediated neovascular endothelial activation and tumor cell damage in cancer of endothelial origin, or cancer with a major neo-angiogenic component.
AB - A polysaccharide toxin, GBS toxin, is produced by group B Streptococcus (GBS) isolates from neonates who died of 'early-onset disease'. GBS toxin, named CM101 in the clinic, was hypothesized, on the basis of our previous in vivo studies, to induce inflammation in pulmonary neovasculature in neonates by crosslinking of embryonic receptors still expressed after birth and in tumor neovasculature in adults. Immunohistochemical in vitro analysis of human biopsies showed that tumor neovasculature is indeed a binding site for CM101. In vivo studies in mice have demonstrated that CM101 induced inflammatory responses in neoplastic tumor neovasculature causing inhibition of tumor growth and tumor cell necrosis. These experimental observations warranted a phase 1 clinical trial for CM101 as an anti-neovascularization agent in human cancer therapy. Cancer patients received one cycle of therapy consisting of three treatments during 1 week. CM101 was administered over 15 min by i.v. infusion. Dosages of 7.5 μg/kg (1 U/kg), n = 3; 15 μg/kg (2 U/kg), n = 6; 24.75 μg/kg (3.3 U/kg), n = 3; and 37.5 μg/kg (5 U/kg), n = 3 were used. Enzyme-linked immunosorbent sandwich assays (ELISA) of the patients' sera showed a marked elevation of soluble E-selectin with a peak concentration observed at 8-12 h after each CM101 infusion. The average baseline value for soluble E-selectin prior to the first treatment was 97.3 ± 23.4 ng/ml (mean ± SEM, n = 15) and the average peak level at 8 h was 441.6 ± 62.4 (mean ± SEM, n = 15; P < 0.001). Subsequent treatments gave average maximum soluble E-selectin levels again at 8 h of 466.9 ± 87.6 and 412.0 ± 67.8 ng/ml, for treatments 2 and 3 respectively. Baseline values for treatments 2 and 3 were 192.3 ± 26.4 and 226.4 ± 26.1 ng/ml respectively (p < 0.01 versus treatment 1). Out of 15 patients, 5 showed tumor reduction or stabilization and were given additional cycles of therapy. CM101 induced an increase in soluble E-selectin levels, which remained elevated over baseline at the start of the following treatment cycles. The baseline remained elevated for several weeks after the final treatment, i.e., P < 0.01 for levels before treatment 1 compared to those at week 4 after treatment. Elevated soluble E-selectin is considered proof of endothelial engagement in an inflammatory process. Our data support the contention that the inflammatory response observed in these cancer patients is targeting the tumor neovasculature and that measurement of soluble E-selectin levels in patients treated with CM101 can provide important information on the magnitude of CM101-mediated neovascular endothelial activation and tumor cell damage in cancer of endothelial origin, or cancer with a major neo-angiogenic component.
KW - CM101
KW - GBS toxin
KW - angiogenesis
KW - cancer
KW - inflammation
KW - neovascularization
UR - http://www.scopus.com/inward/record.url?scp=0030986163&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030986163&partnerID=8YFLogxK
U2 - 10.1007/s004320050046
DO - 10.1007/s004320050046
M3 - Article
C2 - 9119883
AN - SCOPUS:0030986163
SN - 0171-5216
VL - 123
SP - 173
EP - 179
JO - Journal of Cancer Research and Clinical Oncology
JF - Journal of Cancer Research and Clinical Oncology
IS - 3
ER -