Lanreotide Depot: An Antineoplastic Treatment of Carcinoid or Neuroendocrine Tumors.

PURPOSE: Peptide drugs for antineoplastic therapies usually have low oral bioavailability and short in vivo half-lives, requiring less preferred delivery methods. Lanreotide depot is a sustained-release somatostatin analog (SSA) formulation produced via an innovative peptide self-assembly method. Lanreotide is approved in the USA and Europe to improve progression-free survival (PFS) in patients with unresectable gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and also approved in Europe for symptom control in carcinoid syndrome associated with GEP-NETs. This review discusses how the distinct molecule and formulation of lanreotide depot provide advantages to patients and health care providers, as well as the most recent clinical evidence demonstrating the safety and efficacy of lanreotide depot in inhibiting tumor growth and controlling hormonal symptoms in GEP-NETs. METHODOLOGY AND RESULTS: The lanreotide depot formulation confers a remarkable pharmacokinetic profile with no excipients, comprised only of lanreotide acetate and water. Of note, lanreotide depot constitutes an example for peptide self-assembly based formulations, providing insights that could help future development of sustained-release formulations of other antineoplastic peptides. Most patients with GEP-NETs will present with inoperable or incurable disease; thus, medical management for symptoms and tumor control plays a crucial role. Recent long-term clinical studies have demonstrated that lanreotide depot is well tolerated, prolongs PFS in GEP-NET patients, and significantly reduces symptoms related to carcinoid syndrome. CONCLUSIONS: The unique depot formulation and delivery method of lanreotide confer advantages in the treatment of metastatic GEP-NETs, contributing to improvements in NET-related symptoms and PFS without reducing quality of life in this patient population.

In vivo progestin treatments inhibit nitric oxide and endothelin-1-induced bovine endometrial prostaglandin (PG) E (PGE) secretion in vitro.

Synchronization of estrus with progestins in cows has been reported to inhibit nitric oxide (NO) and endothelin-1 (ET-1)-stimulated bovine luteal PGE secretion without affecting prostaglandin F2alpha (PGF2alpha) secretion in vitro [Weems YS, Randel RD, Tatman S, Lewis A, Neuendorff DA, Weems CW. Does estrous synchronization affect corpus luteum (CL) function? Prostaglandins Other Lipid Mediat 2004;74:45-59]. Two experiments were conducted to determine the effects of NO donors, endothelin-1 (ET-1), and NO synthase (NOS) inhibitors on bovine caruncular endometrial secretion of PGE and PGF2alpha in vitro. In Experiment 1, estrus was synchronized in Brahman cows with Synchromate-B ear implants, which contained the synthetic progestin norgestamet. Days 14-15 caruncular endometrial slices were weighed, diced, and incubated in vitro with treatments. Treatments (100 ng/ml) were: Vehicle (control), l-NAME (NOS inhibitor), l-NMMA (NOS inhibitor), DETA (control), DETA-NONOate (NO donor), sodium nitroprusside (NO donor), or ET-1. In Experiment 2, estrus was synchronized in Brahman cows with either Lutalyse (PGF2alpha) or a controlled intravaginal drug releasing device (CIDR-containing progesterone) or estrus was not synchronized. Days 14-15 caruncular endometrial slices were weighed, diced, and incubated in vitro with treatments. Treatments (100 ng/ml) were: vehicle, l-NAME, l-NMMA, DETA, DETA-NONOate, sodium nitroprusside, SNAP (NO donor) or ET-1. Tissues were incubated in M-199 for 1h without treatments and with treatments for 4 and 8h in both experiments. Media were analyzed for concentrations of PGE and PGF2alpha by radioimmunoassay (RIA). Hormone data in Experiments 1 and 2 were analyzed by 2x7 and 3x2x8 factorial design for ANOVA, respectively. Concentrations of PGE and PGF2alpha in media increased (P< or =0.05) from 4 to 8 h regardless of treatment group in Experiment 1, but did not differ (P> or =0.05) among treatments. In Experiment 2, concentrations of PGE and PGF2alpha increased (P< or =0.05) with time in all treatment groups of all three synchronization regimens. DETA-NONOate, SNAP, and sodium nitroprusside (NO donors) and ET-1 increased caruncular endometrial (P< or =0.05) secretion of PGE2 in unsynchronized and Lutalyse synchronized cows, but not when estrus was synchronized with a CIDR (P> or =0.05). No treatment increased (P> or =0.05) PGF2alpha in any synchronization regimen. It is concluded that norgestamet in Synchromate-B ear implants or progesterone in a CIDR alters NO or ET-1-induced secretion of PGE by bovine caruncular endometrium and could interfere with implantation by altering the PGE:PGF2alpha ratio resulting in increased embryonic losses during early pregnancy.