Synthesis and biological evaluation of taxinine analogues as orally active multidrug resistance reversal agents in cancer.
Three novel taxinine analogues were prepared and tested for their activity as multidrug resistance (MDR) reversal agents in comparison with verapamil. In vitro testing demonstrated that compounds 8-10 possess MDR-reversal activity in the KB/V cell line. Half-hour after treatment with 5, 10, and 20 micromol/L compound 9, the intracellular rhodamine123 concentration increased 2.3, 2.9, and 3.2-fold, respectively, higher than 1.88-fold of 10 micromol/L verapamil in KB/V cell line. In vivo studies with VCR-resistant KB/V tumor xenografts showed that compound 9 in combination with VCR significantly inhibited tumor growth. Treatment with VCR or 9 alone did not result in growth inhibition. These results reveal that three taxinine analogues are good modifiers of MDR in tumor cells.
Department of Pharmacology, Institute of Materia Medica, Chinese Academic of Medical Science and Peking Union Medical College, 1 Xian Nong Tan Street, Beijng 100050, China.
Xin
X
Zhao
Jun
J
Gu
Dali
D
Yin
Xiaoguang
X
Chen
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D043823:Taxoids / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D013997:Time Factors; D014750:Vincristine / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D043823:Taxoids; D014750:Vincristine; C473166:taxinine