Vitamin D analogs: new therapeutic agents for the treatment of squamous cancer and its associated hypercalcemia.
We have examined the in vitro effects of 1,25 dihydroxy-vitamin D3 [1,25(OH)2D3] and of two side-chain modified analogs of 1,25(OH)2D3 (EB1089 and MC903) on cell growth and parathyroid hormone related peptide (PTHRP) production in immortalized (HPK1A) and neoplastic (HPK1A-ras) keratinocytes. Cell proliferation was strongly inhibited by 1,25(OH)2D3 and its analogs in HPK1A cells, and in this system EB1089 was 10-100 times more potent than 1,25(OH)2D3 or MC903. A similar effect on cell proliferation was observed in HPK1A-ras cells; however, 10-fold higher concentrations of 1,25(OH)2D3 or its analogs were required. We also observed a strong and dose-dependent inhibitory effect of these compounds on PTHRP secretion and gene expression. In both immortalized and neoplastic keratinocytes, EB1089 was 10-100 times more potent than 1,25(OH)2D3 or MC903 on inhibiting PTHRP production. However, although effective in HPK1A-ras cells, 10-fold higher concentrations of 1,25(OH)2D3 or its analogs were required to produce similar actions in this neoplastic model. These studies therefore demonstrate that a 1,25(OH)2D3 analog with low calcemic potency in vivo (EB1089) can inhibit keratinocyte proliferation and PTHRP production by such cells with greater potency than 1,25(OH)2D3. The observed effects of such analogs in neoplastic keratinocytes predicts their potential usefulness in vivo in inhibiting squamous cancer growth and its associated hypercalcemia.
Yu
J
J
Department of Medicine, McGill University, Montreal, Quebec, Canada.
Papavasiliou
V
V
Rhim
J
J
Goltzman
D
D
Kremer
R
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed / Q000187:drug effects; D002472:Cell Transformation, Viral; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006934:Hypercalcemia / Q000188:drug therapy / Q000209:etiology; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009368:Neoplasm Transplantation; D044162:Parathyroid Hormone-Related Protein; D014176:Protein Biosynthesis; D012878:Skin Neoplasms / Q000150:complications / Q000188:drug therapy*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; C055085:calcipotriene; D002117:Calcitriol; C078903:seocalcitol