Membrane disrupting lytic peptide conjugates destroy hormone dependent and independent breast cancer cells in vitro and in vivo.

We have prepared conjugates of a membrane disrupting lytic peptide (hecate) and a 15-amino acid segment of the beta-chain of CG and hecate and the decapeptide, luteinizing hormone releasing hormone (LHRH). We have tested the concept that these conjugates will target breast cancer cells expressing LH/CG or LHRH receptors. In previous studies, we were able to destroy prostate cancers in vitro and in vivo with lytic peptide conjugates. Hecate, hecate-betaCG and LHRH-hecate were added to cultures of the human breast cancer cell lines MCF-7 and MDA-MB-435S. Hecate and its conjugates showed concentration dependent toxicity to both cell lines. The lytic peptide alone showed similar EC50 values for both cell lines; however, there was a significant difference between the EC50 values when the conjugates were tested. The hormone dependent MCF-7 cell line was less sensitive to the betaCG conjugate than to the LHRH conjugate; the reverse was found for the hormone independent MDA-MB-435S cells. Removal of steroids decreased the sensitivity of MCF-7 cells to both lytic peptide conjugates and this sensitivity could be restored by adding estradiol. Activation of protein kinase C further increased the sensitivity to the drug. MDA-MB-435S xenografts were established in intact female athymic nude mice, which were treated once a week for 3 weeks with hecate-betaCG via the lateral tail vein. The ability of hecate-betaCG to destroy xenografts of human breast cancer cells (MDA-MB-435S) in nude mice was demonstrated for the first time. We conclude that hecate-betaCG and LHRH-hecate conjugates could serve as useful drugs for the treatment of breast cancer.

Embarazo ectópico ovárico tras transferencia embrionaria intrauterina ecoguiada resuelto de forma conservadora por laparoscopia / Ovarian ectopic pregnancy after intrauterine embryonic transfer resolved conservatively by laparoscopy

Presentamos un caso de embarazo ectópico tras fecundación in vitro y transferencia intrauterina guiada por ecografía. El ascenso de la gonadotropina coriónica humana (HCG), asociado a la ecografía hizo sospechar la presencia del embarazo ectópico. La laparoscopia diagnóstica halló unas trompas normales y una tumoración ovárica izquierda de 3-4 cm compatible con un cuerpo lúteo hemorrágico o ectópico ovárico. El tratamiento conservador por laparoscopia del embarazo permitió conservar la funcionalidad de ese ovario. La transferencia de embriones ecoguiada no evita el embarazo ectópico a pesar de asegurarnos la correcta ubicación de los embriones, tal como muestra nuestro caso (AU)

hCG beta residues 94-96 alter LH activity without appearing to make key receptor contacts.

The ability of human chorionic gonadotropin (hCG) to distinguish lutropin (LHR) and follitropin (FSHR) receptors is controlled principally by beta-subunit residues 94-117. To learn how residues 94-96 (Arg-Arg-Ser) influence LHR binding, we studied the effects of replacing them on the LH and FSH activities of a bifunctional hCG analog in which residues 101-109 were derived from FSH. Analogs containing 1-3 arginines and no aspartates at residues 94-96 bound LHR with 25-400% the potency of hCG. When residues 94-96 were neutral or contained 1-3 aspartates, LHR binding was reduced 6-100 fold but remained at least ten-fold greater than the negative control analog containing residues 94-117 derived from FSH. Residues 94-96 had little influence on FSHR binding. These observations support a model [Moyle et al. (1995) J. Biol. Chem. 270:20,020] in which residues 94-96 influence LHR binding specificity primarily through an effect on hormone conformation rather than by direct participation in essential high affinity receptor contacts.