Targeted destruction of prostate cancer cells and xenografts by lytic peptide-betaLH conjugates.
In series of experiments conducted in vitro, we have established the concept that conjugates of the lytic peptides Hecate or Phor14 with a fragment of the beta chain of LH (amino acids 80-94) selectively destroy both androgen sensitive and insensitive human prostate cancer cells. Extraction of steroids from the culture medium by charcoal reduced the ability of the conjugates to kill LNCaP, BRF41T and PC-3 cells. Addition of hormones known to up-regulate LH receptors (estradiol, testosterone or FSH) to the culture medium restored the ability of the conjugates to kill these cell lines. The toxicity of the conjugates (EC(50)) to these cell lines was closely correlated to their LH binding capacities (f mol/10(6) cells). In series of in vivo experiments we have shown that both the Hecate and Phor14-betaLH conjugates are remarkably effective in causing tumor cell necrosis and cessation of tumor growth in nude athymic mice. Treatment with Hecate-betaLH (12 mg/kg body weight) resulted in a reduction of tumor burden (mg tumor/g body weight) from 60 to 14 (P<0.0001); treatment with Phor14-betaLH (12 mg/kg body weight) reduced tumor burden to 27 mg (P<0.0001). Treatment with a high dose of Phor14-betaLH (24 mg/kg body weight) reduced the tumor burden from 60 to 12 mg/kg P<0.0001). Pretreatment of animals receiving a low dose of Phor14-betaLH (12 mg/kg) with either estradiol or follicle stimulating hormone, (FSH) resulted in reduction of tumor burden from 60 to 11 mg/kg. Administration of a second 3-week treatment after a one month recovery period caused complete regression of more than 75 percent of the tumors. No changes in body weight or histological abnormalities were found in any of the organs examined, except the testes.
Hansel
W
W
Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA. hanselw@pbrc.edu
Leuschner
C
C
Gawrońska
B
B
Enright
F
F
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D016466:CHO Cells; D016923:Cell Death / Q000187:drug effects; D006224:Cricetinae; D004958:Estradiol / Q000008:administration & dosage; D005640:Follicle Stimulating Hormone / Q000008:administration & dosage; D015870:Gene Expression; D006801:Humans; D037101:Luteinizing Hormone, beta Subunit / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000737:chemistry; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011974:Receptors, LH / Q000235:genetics; D011993:Recombinant Fusion Proteins; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D037101:Luteinizing Hormone, beta Subunit; D010446:Peptide Fragments; C480516:Phor14-betaLH; D011974:Receptors, LH; D011993:Recombinant Fusion Proteins; C480515:hecate-betaLH; D004958:Estradiol; D005640:Follicle Stimulating Hormone; D008668:Metallothionein