Li-Chun Sun and David H. Coy Pages 2 - 10 ( 9 )
Somatostatin receptors (SSTRs), especially SSTR subtype 2, are found expressed at relatively higher levels in many tumor cells and in tumoral blood vessels relative to normal tissues. This creates an opportunity for developing various cytotoxic SST conjugates that selectively target SSTR2-specific sites. Accordingly, some potent chemotherapeutic agents such as camptothecin (CPT), methotrexate (MTX), paclitaxel (PTX) and doxorubicin (DOX) have been coupled to SSTR2-preferential somatostatin (SST) analogs. These new cytotoxic SST conjugates display significant SSTR-selective anti-tumor abilities in many different types of tumors. For instance, the CPT-SST conjugate JF-10-81, in which CPT is coupled to the N-terminus of a SSTR2-specific SST analog (JF-07-69), had wide ranging anti-tumor and anti-angiogenic ability. This conjugate also showed an ability to overcome multi-drug resistance (MDR) in SSTR-over-expressing and CPT-insensitive human pancreatic carcinoid BON cells. Notably, another DOX-SST conjugate, AN-238, made by coupling pyrrolino-DOX to the SST analog RC-121, displayed indirect anti-tumor activity against SSTR-negative, non-small cell lung cancer H-157 tumor growth by directly targeting SSTR-positive tumoral vessels of host mice. These cytotoxic SST conjugates should deliver chemotherapeutic agents to receptor-specific sites, enhance anti-tumor efficacy, reduce toxic side effects to normal tissues, and to some extent, overcome MDR. These and other peptide conjugates may possibly represent a newer generation of receptor-targeted cancer therapeutics. This review discusses the progress with reference to SST-based and SSTR-selective cytotoxic cancer therapy.
Somatostatin, somatostatin receptors, conjugates, cancer therapy, bombesin, luteinizing hormone releasing hormone, LHRH, somatotropin release-inhibiting factor, SRIF, neuroendocrine tumors, lanreotide, octreotide, vapreotide, SSTRs, topotecan, irinotecan, neuroblastoma IMR32, pancreatic cancer CFPAC-1, multi-drug resistance-associated protein, breast cancer-resistant protein, HUVECs, Paclitaxel, 2PTX-OCT, doxorubicin, 2-pyrrolino-DOX, Methotrexate, SSTR-negative CHO cells, combretastatin, colchicine
Peptide Research Laboratories, Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.