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The cells were either pretreated with ABT, treated simultaneously with ABT or treated with ABT after the carboplatin. Pretreatment of the cells or simultaneous treatment of the cells with ABT did not significantly increase sensitivity to carboplatin.If the cells were treated with ABT after treatment with carboplatin, an increase in sensitivity was observed. Inhibition of IGROV xenograft growth by carboplatin and ABT.To determine whether ABT could sensitize tumor cells in vivo to carboplatin, IGROV xenografts were established in nude mice.Once tumors were well established, treatment commenced with either carboplatin, or both carboplatin and ABT.All these treatments seemed to be well tolerated with decrease in mean body weights over the duration of the experiment.When used as single agents, both ABT and carboplatin had a modest effect. However, the tumor volume following treatment with both ABT and carboplatin was substantially reduced, with little increase in volume from that observed immediately prior to treatment.To confirm these data, after days of treatment, six representative tumors were excised and their mass determined.Both ABT and carboplatin reduced tumor mass compared with that measured in animals treated with vehicle alone. An at least additive effect was observed in tumors collected from animals which were treated with the drug combination. The lack of significant tumor regression may reflect the submaximal dose of carboplatin used; this dose was selected to allow the detection of any increase in tumor growth inhibition resulting from the inclusion of ABT.This model is consistent with the observations that ABT increases sensitivity to carboplatin, reduces the time to apoptosis, as well as with ABT being most effective if present after treatment with carboplatin.This contrasts with scheduling experiments done with the epidermal growth factor receptor inhibitor gefitinib in which pretreatment with gefitinib causes sensitization to paclitaxel. Although in several cell lines, ABT caused an evident increase in the sensitivity to carboplatin, in some cell lines, this was modest or absent.For example, no sensitization of A cells was observed.This cell line was originally derived by prolonged exposure of A cells to cisplatin.IGROV cells were treated with a range of concentrations of carboplatin and either pretreated, cotreated, or subsequently treated with. Rectangular boxes represent a new addition of drugs, cells were treated for hwith carboplatin and ABT, then washed, and retreated with fresh ABT.Results representative of three separate experiments.This was reflected both as an increase in the measured potency of carboplatin but also as a reduction in the time at which cell death is observed either morphologically by counting cell number, by cleavage of PARP, or by nucleosome formation.ABT was most effective when present after cells were treated with carboplatin, consistent with ABT potentiating the induction of apoptosis triggered by DNA damage and ABT could be combined with carboplatin to Glumetinib enhance the inhibition of tumor xenograft growth.When tested as a single agent in ovarian cancer cells, ABT displayed modest cytotoxiccytostatic activity observed in small cell lung cancer and leukemia cells. Why ovarian cancer cells are markedly less sensitive to ABT is not clear but it might reflect the expression of regulators of the intrinsic apoptosis pathway in different cell types.

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