Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two CPT-SSA conjugates, JF-10-71 and JF-10-81, containing a chemically adjustable release-rate carbamate linker, have been reported previously by us to potently inhibit growth of human neuroblastoma IMR32 cells overexpressing somatostatin receptor type II (SSTR2) but are stable under buffer incubation conditions or in rat plasma. Further experiments now reveal that the conjugates performed well against many additional cell lines, particularly somatostatin receptor containing rat pancreatic CA20948 cells that were actually more sensitive to the conjugates than free camptothecin itself. JF-10-71 and JF-10-81 also were examined for their inhibitory effects on the growth of this and several other tumors transplanted into rats (CA20948) or nude mice. CA20948 tumors, known to overexpress SSTR2 and grown in Lewis rats, were treated, respectively, with nontoxic 400 nmol/kg intraperitoneal (i.p.) doses of JF-10-71 or JF-10-81. Also, SSTR2-positive human SCLC NCI-H69 tumors transplanted in nude mice were treated in a similar fashion. Human prostate PC-3 tumors, which do not contain high concentrations of SSTR2, also were grown in nude mice and treated with a 400 nmol/kg ip dose of JF-10-71. Both cytotoxic conjugates significantly inhibited growth of SSTR2-specific pancreatic and SCLC tumors, but JF-10-81 did not significantly affect PC-3 tumor growth. These experimental results suggested that CPT-SSA conjugates can effectively target and kill tumor cells growing in vivo and that the effect is mediated by somatostatin receptors resulting in either release of camptothecin at the cell surface or, more likely, after receptor-mediated cellular internalization.
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PMID:Effects of camptothecin conjugated to a somatostatin analog vector on growth of tumor cell lines in culture and related tumors in rodents. 1537 Nov 4

The role of Notch signaling in cervical cancer is seemingly controversial. To confirm the function of Notch signaling in this type of cancer, we established a stable Notch1-activated cervical cancer HeLa cell line. We found that Notch1 activation resulted in apoptosis, cell cycle arrest, and tumor suppression. At the molecular level, we found that a variety of genes associated with cyclic AMP, G protein-coupled receptor, and cancer signaling pathways contributed to Notch1-mediated tumor suppression. We observed that the expression of somatostatin (SST) was dramatically induced by Notch1 signaling activation, which was accompanied by enhanced expression of the cognate SST receptor subtype 1 (SSTR1) and SSTR2. Certain genes, such as tumor protein 63 (TP63, p63), were upregulated, whereas others, such as B-cell lymphoma 2 (BCL-2), Myc, Akt, and STAT3, were downregulated. Subsequently, knockdown of Notch1-induced SST reversed Notch1-induced decrease of BCL-2 and increase of p63, indicating that Notch1-induced tumor suppression may be partly through upregulating SST signaling. Our findings support a possible crosstalk between Notch signaling and SST signaling. Moreover, Notch-induced SSTR activation could enhance SSTR-targeted cancer chemotherapy. Valproic acid (VPA), a histone deacetylase inhibitor, suppressed cell growth and upregulated the expression of Notch1 and SSTR2. A combination therapy with VPA and the SSTR2-targeting cytotoxic conjugate CPT-SST strongly led to greater suppression, as compared to each alone. Our findings thus provide us with a promising clinical opportunity for enhanced cancer therapy using combinations of Notch1-activating agents and SSTR2-targeting agents.
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PMID:Notch1-mediated tumor suppression in cervical cancer with the involvement of SST signaling and its application in enhanced SSTR-targeted therapeutics. 2229 Oct 92