Daunorubicin and doxorubicin but not BCNU have deleterious effects on organotypic multicellular spheroids of gliomas

Kaaijk, Patricia; Troost, Dirk; Boer, Onno J. de; Amstel, Paul van; Bakker, Piet; Leenstra, Sieger; Bosch, Dirk

doi:10.1038/bjc.1996.336

Cited by 15 publications

(9 citation statements)

References 17 publications

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“…Moreover, the cytotoxicity of doxorubicin in organotypic multicellular spheroids of human gliomas appeared to be higher than that of BCNU (carmustin). 56 We have recently demonstrated that the toxicity of doxorubicin bound to nanoparticles was rather lower than that of a solution of doxorubicin in saline. 35 In the present study, we found only limited systemic toxicity that was dose-dependent and obviously not enhanced but rather alleviated by polysorbate coating of nanoparticles.…”

Section: No Indication Of Drug-related Neurotoxicitymentioning

confidence: 99%

Chemotherapy of glioblastoma in rats using doxorubicin‐loaded nanoparticles

Steiniger

Kreuter

Khalansky

et al. 2004

Intl Journal of Cancer

400

214

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Glioblastomas belong to the most aggressive human cancers with short survival times. Due to the blood-brain barrier, they are mostly inaccessible to traditional chemotherapy. We have recently shown that doxorubicin bound to polysorbate-coated nanoparticles crossed the intact blood-brain barrier, thus reaching therapeutic concentrations in the brain. Here, we investigated the therapeutic potential of this formulation of doxorubicin in vivo using an animal model created by implantation of 101/8 glioblastoma tumor in rat brains. Groups of 5-8 glioblastoma-bearing rats (total n ‫؍‬ 151) were subjected to 3 cycles of 1.5-2.5 mg/kg body weight of doxorubicin in different formulations, including doxorubicin bound to polysorbate-coated nanoparticles. The animals were analyzed for survival (% median increase of survival time, Kaplan-Meier). Preliminary histology including immunocytochemistry (glial fibrillary acidic protein, ezrin, proliferation and apoptosis) was also performed. Rats treated with doxorubicin bound to polysorbate-coated nanoparticles had significantly higher survival times compared with all other groups. Over 20% of the animals in this group showed a long-term remission. Preliminary histology confirmed lower tumor sizes and lower values for proliferation and apoptosis in this group. All groups of animals treated with polysorbatecontaining formulations also had a slight inflammatory reaction to the tumor. There was no indication of neurotoxicity. Additionally, binding to nanoparticles may reduce the systemic toxicity of doxorubicin. This study showed that therapy with doxorubicin bound to nanoparticles offers a therapeutic potential for the treatment of human glioblastoma.

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Section: No Indication Of Drug-related Neurotoxicitymentioning

confidence: 99%

Chemotherapy of glioblastoma in rats using doxorubicin‐loaded nanoparticles

Steiniger

Kreuter

Khalansky

et al. 2004

Intl Journal of Cancer

400

214

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“…In several studies, tumor fragment spheroids were shown to maintain tumor markers and viability better than either monolayers or multicellular spheroids (12)(13)(14)17). In a few cases, the effect of different treatments has been studied-for example, on the proliferation or histology of the tumor (13,(18)(19)(20). We are not aware of any study in which tumor fragment spheroids were specifically examined for apoptosis, although this in vitro model has much promise for such studies.…”

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confidence: 99%

A Novel In Vitro Model of Human Mesothelioma for Studying Tumor Biology and Apoptotic Resistance

Kim

Wilson²,

Abayasiriwardana³

et al. 2005

Am J Respir Cell Mol Biol

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Like many tumors, malignant mesothelioma exhibits significant chemoresistance and resistance to apoptosis in vivo that is not seen in current in vitro models. To study the mechanisms of this multicellular resistance, biologically relevant in vitro models are necessary. Therefore, we characterized and tested human mesothelioma tissue grown in vitro as tumor fragment spheroids. After 5-10 d in culture, fragments from each of 15 human mesothelioma tumors rounded into spheroids. The tumor fragment spheroids maintained multiple characteristics of the original tumors for up to 3 mo including the presence of viable mesothelioma cells, macrophages, and a collagenrich stroma. In 14-d-old spheroids, mesothelioma cells showed the same proliferation rate and expression of a death receptor, DR5, as in the original tumor. To determine responses to treatment, we treated tumor fragment spheroids grown from three separate tumors with agents, TNF-related apoptosis-inducing ligand (TRAIL) plus cycloheximide, that induced near total apoptosis in three human mesothelioma cell lines (M28, REN, MS-1) grown as monolayers (94 Ϯ 6% apoptosis; mean Ϯ SEM). Compared with mesothelioma cells in monolayers, mesothelioma cells in the spheroids were resistant to TRAIL plus cycloheximide (32 Ϯ 4% apoptosis; mean Ϯ SEM). Apoptotic resistance of mesothelioma cells was significantly reduced by inhibiting either the PI3K/Akt pathway with LY294002 (47 Ϯ 6% apoptosis) or the mTOR pathway with rapamycin (50 Ϯ 17% apoptosis). We conclude that human mesothelioma can be maintained in vitro in a biologically relevant model that exhibits apoptotic resistance, thereby permitting study of its tumor biology and of novel approaches to therapy. Keywords: collagen; death receptor DR5; mTOR; multicellular resistance; PI3K/Akt survival pathway; TNF-related apoptosis-inducing ligand (TRAIL); tumor-associated macrophage; tumor fragment spheroid Resistance to apoptosis, or programmed cell death, is now considered to be a critical step in the generation and maintenance of cancer (1). Resistance to apoptosis may underlie the resistance of tumors to chemotherapy and radiotherapy (2). Mechanisms of resistance have been identified on a cellular level, for example via P-glycoprotein efflux pumps, DNA repair mechanisms, or from expression of anti-apoptotic proteins such as Bcl-2 (3). Additional mechanisms of resistance are now recognized to involve stimuli from the cell's external environment, termed multicellular resistance (3). These multicellular resistance mechanisms have been attributed to cell-cell contacts, cell-matrix contacts, and the three-dimensional shape found in tissues but (Received in original form November 14, 2004 and in final form July 30, 2005) *These authors contributed equally to this work. Two types of in vitro models used to study the complex resistance found in tumors are multicellular spheroids and tumor fragment spheroids (5, 6). In the first, cells are allowed to grow into three-dimensional structures called multicellular spheroids (5). In thes...

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“…More recently, the therapeutic effect and diffusion of various selectively replicative (Bauerschmitz et al, 2002;Grill et al, 2002) and nonreplicative (Enger et al, 2002;van Beusechem et al, 2002) viral gene therapy vectors have been studied. Even though systematic studies of the binding, distribution, and chemotherapeutic effect of 23 Engineering Lipid Vesicles of Enhanced Intratumoral Transport Capabilities doxorubicin and daunorubicin (Kaaijk et al, 1996;Wartenberg et al, 1998), two therapeutic molecules clinically used in their liposome-encapsulated form for treatment of Kaposi sarcomas and being developed also for other cancer types (Tejada-Berges et al, 2002), have been published, no systematic study has described the interaction of tumor spheroids with delivery systems or liposomes in particular.…”

Section: Discussionmentioning

confidence: 99%