Subcellular localisation of the antitumour drug mitoxantrone and the induction of DNA damage in resistant and sensitive human colon carcinoma cells

Abstract

Cellular uptake and subcellular localisation of the antitumour agent mitoxantrone were studied in a human colon-carcinoma cell line and a mitoxantrone-resistant subline showing features consistent with an atypical multidrug-resistance phenotype involving altered topoisomerase II. Flow cytometry indicated a reduced uptake of mitoxantrone in the resistant line. Confocal microscopy indicated that mitoxantrone-associated fluorescence was primarily found within discrete cytoplasmic inclusions and around the periphery of the nucleus, with low levels being observed within the nucleus. The frequency of cytoplasmic inclusions was reduced in mitoxantrone-resistant cells as compared with parental cells. Fluorescence in cytoplasmic inclusions persisted throughout a 24-h post-treatment period in both cell lines. The results suggest that the persistence of mitoxantrone in cells is a determinant for the continuous induction of DNA damage, perhaps through chronic topoisomerase II trapping, and that modified sequestration may contribute to clinically relevant moderate levels of non-classic multidrug resistance.

Combined percutaneous ethanol injection and mitoxantrone versus radiofrequency ablation in the treatment of hepatocellular carcinoma

“…In group II there were 49 lesions (81.7%) still showing stationary course, where 1 patient (1.7%) showed local recurrence. These good results in injection group were explained by Fox and Smith [31] who selected mitoxantrone for local treatment of malignant liver lesions because of its low tissue toxicity, high intra tumor concentration after intra tumor instillation, and long time in the tumor, since it has a tendency to remain at the application site.…”

“…It is used as an anticancer agent and has demonstrated clinical activity when administered via multiple routes: intravenous, intraperitoneal, intrapleural, intrapericardial, or intrathecal [6]. Mitoxantrone was selected for palliative local treat ment of malignant liver lesions because of its low tissue toxicity, high intratumoral concentration after intratumoral instillation, since it has a tendency to remain at the application site [7].…”

Spectral analysis of the DNA targeting bisalkylaminoanthraquinone DRAQ5 in intact living cells

“…The anticancer agent mitoxantrone and modified anthraquinones show variable DNA-affinic and cell-permeation properties (5,(24)(25)(26)(27), with the probe DRAQ5 readily crossing the plasma membrane of intact living cells (5,6). The current study on this 1,5-bisalkylaminoanthraquinone has addressed target binding and spectral properties in live cells.…”

Characteristics of a novel deep red/infrared fluorescent cell-permeant DNA probe, DRAQ5, in intact human cells analyzed by flow cytometry, confocal and multiphoton microscopy

“…The principal member of this group is the anticancer anthraquinone, mitoxantrone, which has been found to demonstrate pH-dependent but extremely weak fluorescence (3). Intact mitoxantronetreated human and murine cells exhibit low levels of fluorescence (4,5). Importantly, 647 nm wavelength laser light can be used to optimally excite mitoxantrone and related anthraquinones with fluorescence detection into the low infrared regions of the emission spectrum (6), providing a rationale for the use of such agents in multiparameter analayses involving visible range fluorochromes.…”