title: Preclinical in vivo efficacy of two 9-dihydrotaxane analogues against human and murine tumours.
abstract: Two 9-dihydrotaxane analogues were synthesised and tested for in vitro potency and in vivo efficacy against murine and human tumour xenografts in mice. The in vitro potency of 9-dihydrotaxol (9-DH-t) and 10-deacetyl-9-dihydrotaxol (10-DeAc-9-DH-t) was generally less than that of paclitaxel against human and murine tumour cells. However, both analogues were at least 20-fold more soluble than paclitaxel in water. The analogues yielded cure rates > or = 60% against human MX-1 solid tumour xenografts in mice, compared with a cure rate of 10% for mice treated with paclitaxel. Both of the analogues were more effective than paclitaxel for treatment of murine M109 solid tumour in mice. 10-DeAc-9-DH-t was as effective as paclitaxel against murine B16 ascites tumour, while 9-DH-t was less effective. Both 10-DeAc-9-DH-t and 9-DH-t were demonstrably less toxic than paclitaxel. At equal dosages 9-DH-t produced serum concentrations greater than paclitaxel, while 10-DeAc-9-DH-t yielded serum concentrations less than paclitaxel. However, the decrease in toxicity of 9-DH-t and 10-DeAc-9-DH-t allowed a 4-fold increase in daily dosage. These two 9-dihydrotaxane analogues yielded favourable preclinical data and demonstrated good potential for further development.
authors.affiliation: Abbott Laboratories, Abbott Park IL, 60064-3500, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Alder
authors.forename: K P
authors.initials: KP
authors.lastname: Jarvis
authors.forename: K C
authors.initials: KC
authors.lastname: Marsh
authors.forename: L L
authors.initials: LL
authors.lastname: Klein
authors.forename: J J
authors.initials: JJ
authors.lastname: Clement
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D043823:Taxoids; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C098224:10-deacetyl-9-dihydrotaxol; D000970:Antineoplastic Agents; D043823:Taxoids; C088970:9-dihydrotaxol; D017239:Paclitaxel