The influence of P-glycoprotein expression and its inhibitors on the distribution of doxorubicin in breast tumors.
The influence of P-glycoprotein expression and its inhibitors on the distribution of doxorubicin in breast tumors.
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DOI：
10.1186/1471-2407-9-356
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发表时间：
2009-10-06
期刊：
影响因子：
3.8
通讯作者：
Tannock IF
中科院分区：
文献类型：
--
作者：
Patel KJ;Tannock IF
抗癌药物通过血管进入实体肿瘤，必须穿透肿瘤组织才能到达所有癌细胞。先前的研究已经证明了随着与血管的距离增加，多柔比星荧光降低的陡峭梯度，使得许多肿瘤细胞不暴露于药物。使用多层细胞培养物的研究表明，增加的P-糖蛋白（PgP）与多柔比星的更好渗透相关，而PgP抑制剂降低了肿瘤组织中的药物渗透。在这里，我们评估PgP表达对阿霉素在体内分布的影响。用多柔比星处理具有高或低PgP表达的肿瘤亚系的小鼠，用或不用PgP抑制剂维拉帕米或PSC 833预处理。使用免疫荧光定量阿霉素相对于肿瘤血管的分布。我们的研究结果表明，与Pgp过表达肿瘤相比，野生型血管附近的细胞对阿霉素的摄取更大，并且用维拉帕米或PSC 833预处理增加了Pgp过表达肿瘤的摄取。然而，与PgP过表达肿瘤相比，野生型肿瘤中多柔比星荧光降低的梯度更陡，用PgP抑制剂治疗PgP过表达肿瘤导致多柔比星分布的梯度更陡和更大的异质性。PgP抑制剂可增加血管附近细胞对阿霉素的摄取，但对中间距离细胞的药物摄取几乎没有影响，可能对减少远端细胞对阿霉素的摄取具有矛盾作用。这种效应可能导致PgP抑制剂在临床试验中的成功有限。
Anti-cancer drugs access solid tumors via blood vessels, and must penetrate tumor tissue to reach all cancer cells. Previous studies have demonstrated steep gradients of decreasing doxorubicin fluorescence with increasing distance from blood vessels, such that many tumor cells are not exposed to drug. Studies using multilayered cell cultures show that increased P-glycoprotein (PgP) is associated with better penetration of doxorubicin, while PgP inhibitors decrease drug penetration in tumor tissue. Here we evaluate the effect of PgP expression on doxorubicin distribution in vivo. Mice bearing tumor sublines with either high or low expression of PgP were treated with doxorubicin, with or without pre-treatment with the PgP inhibitors verapamil or PSC 833. The distribution of doxorubicin in relation to tumor blood vessels was quantified using immunofluorescence. Our results indicate greater uptake of doxorubicin by cells near blood vessels in wild type as compared to PgP-overexpressing tumors, and pre-treatment with verapamil or PSC 833 increased uptake in PgP-overexpressing tumors. However, there were steeper gradients of decreasing doxorubicin fluorescence in wild-type tumors compared to PgP overexpressing tumors, and treatment of PgP overexpressing tumors with PgP inhibitors led to steeper gradients and greater heterogeneity in the distribution of doxorubicin. PgP inhibitors increase uptake of doxorubicin in cells close to blood vessels, have little effect on drug uptake into cells at intermediate distances, and might have a paradoxical effect to decrease doxorubicin uptake into distal cells. This effect probably contributes to the limited success of PgP inhibitors in clinical trials.
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DOI：
10.1111/j.1440-1681.1995.tb01943.x
发表时间：
1995-11-01
影响因子：
2.9
作者：
BAGULEY, BC;FINLAY, GJ
通讯作者：
FINLAY, GJ
影响因子：
3
作者：
DURAND, RE
通讯作者：
DURAND, RE
影响因子：
3
作者：
ERLANSON, M;DANIELSZOLGAY, E;CARLSSON, J
通讯作者：
CARLSSON, J
影响因子：
2.4
作者：
Carlson, Robert W.;O'Neill, Anne M.;Wood, William C.
通讯作者：
Wood, William C.
影响因子：
11.5
作者：
Kyle, Alastair H.;Huxham, Lynsey A.;Minchinton, Andrew I.
通讯作者：
Minchinton, Andrew I.