Effects of Doxorubicin and Cisplatin on Multicellular Tumor Spheroids from Human Lung Cancer

Inoue, Shoichi; Ohnuma, Takao; Takaoka, Kazuo; Suzuki, Yasunosuke; Kaneko, Mamoru; Safirstein, Robert; Holland, James F.

doi:10.1089/cdd.1987.4.213

Cited by 16 publications

(14 citation statements)

References 11 publications

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“…Because 3D multicellular tumor spheroids provide a microenvironment that mimics tumors in vivo, (10) spheroid culture has been used to evaluate tumor cell invasiveness and ⁄ or its responsiveness to anticancer drugs. (11)(12)(13)(14)(15) At IC 10 determined in monolayer culture, both cisplatin or docetaxel did not affect filopodia formation. However, at IC 50 also determined in monolayer culture, docetaxel, but not cisplatin, significantly decreased filopodia formation in HEp-2 cells in spheroid culture (Fig.…”

Section: Resultsmentioning

confidence: 99%

Docetaxel suppresses invasiveness of head and neck cancer cells in vitro

et al. 2010

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The combination of docetaxel, cisplatin, and fluorouracil significantly enhances the survival of head and neck cancer patients compared to cisplatin and fluorouracil. We hypothesized that docetaxel may affect invasiveness of the head and neck cancer cells in addition to its tumor-killing effect. Two different head and neck cancer cell lines (HEp-2 and Ca9-22) were treated with docetaxel at IC 10 and IC 50 concentrations. Cell migration and invasive growth was evaluated by wound healing assay and three-dimensional (3D) culture of multicellular tumor spheroids, respectively. Expression levels of possible downstream effectors for cell migration ⁄ invasiveness were measured by immunoblotting in conditions with or without docetaxel. Docetaxel, but not cisplatin, suppressed filopodia formation compared with no treatment (control) condition. Consistent with this, docetaxel suppressed two-dimensional (2D) cell migration and 3D cell invasion compared with control or cisplatin. Only docetaxel treated cells exhibited thick tubulin bundle and had lower activity of Cdc42, a member of the Rho family of small GTPases. In conclusion, Docetaxel treatment suppressed migration and invasiveness of head and neck cancer cells in vitro, which is likely to be mediated by regulating Cdc42 activity. (Cancer Sci 2010; 101: 1382-1386 S quamous cell carcinoma (SCC) of the head and neck accounts for 5% of cancers in adults worldwide.(1) The disease is potentially curable at an early stage, but most patients present with locally advanced disease. Only 30-50% of patients with locally advanced disease live for 3 years after surgery and radiation therapy. Locoregional recurrences or distant metastases develop in 40-60% of them.(2-5) Moreover, radical resection of the tumor, which results in loss of the larynx, severely compromises quality of life in such patients. In order to increase the survival rate and preserve voice and swallowing function over surgery and radiation alone, various supplementary chemotherapy regimens have been developed. (6)(7)(8) Recently it was reported that the combination of docetaxel, cisplatin, and fluorouracil (TPF) followed by chemoradiotherapy significantly enhances survival of head and neck cancer patients compared to cisplatin and fluorouracil (PF) followed by chemoradiotherapy.(9) Estimates of overall survival at 3 years were 62% in the TPF and 48% in the PF groups. It was also reported that incidence of distant metastasis is lower in the TPF (5% vs 9%), although it does not reach statistical significance. We therefore hypothesized that docetaxel may affect migration and invasiveness of the head and neck cancer cells. The mechanism of antitumor effect of the taxanes, such as docetaxel is thought to be the stabilization of microtubules during mitosis, which leads to blockade of cell division and eventually cell death. However, the effect of docetaxel on cell invasiveness has not been evaluated in head and neck cancers. We demonstrate here that docetaxel inhibited migration of head and neck cancer cells in vitro, ...

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Section: Resultsmentioning

confidence: 99%

Docetaxel suppresses invasiveness of head and neck cancer cells in vitro

et al. 2010

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“…The resistance of MTS to drugs such as DXR (9), methotrexate (10) and bleomycin or peplomycin (11) have been reported to be due mainly to impaired penetration of the drug. Previous work from our laboratory revealed that patterns of DXR-induced cell lethality and the drug penetration depended on tumor cell types (12). Thus, PC-10 human squamous cell carcinoma MTS were progressively more resistant to DXR when their size increased, whereas the susceptibility of PC-6 human small cell carcinoma MTS tended to increase when the MTS grew larger.…”

Section: Introductionmentioning

confidence: 83%

“…The population doubling time of PC-6 cells was approximately 20 hrs and that of PC-10 cells was 23 hrs. MTS production MTS were produced by the method described by Yuhas et al (1,2) with minor modifications (12). One x 105 viable PC-6 or PC-10 cells in 10 ml of the complete medium were placed in 100 mm plastic Petri dishes (No.…”

Section: Cell Linesmentioning

confidence: 99%

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Effects of Physiological Oxygen Environment on Drug-Induced Cell Lethality of Multicellular Tumor Spheroids from Human Lung Cancer

Inoue

Ohnuma²

1989

Selective Cancer Therapeutics

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Advanced malignant tumors of certain histological types contain a hypoxic and necrotic core. Multicellular tumor spheroids (MTS) have the characteristics of chronically hypoxic cells in the center. We studied the effects of physiological oxygen environment on MTS growth and the cell lethality produced by doxorubicin (DXR) and cisplatin (DDP). MTS were made from 2 human lung cancer cell lines; PC-6 small cell and PC-10 squamous cell carcinoma, and grown for 2, 3 or 4 weeks; either in 5% CO2/air or 5% 02/5% CO2/90% N2. They were exposed to graded concentrations of DXR for 1 hr and cell lethality was determined by clonogenic assay. In the physiological oxygen environment MTS growth was retarded for both cell lines. PC-6 MTS grown in physiological oxygen environment were more sensitive to DXR than those developed in air. The differential sensitivity was most pronounced with the 2 week old MTS and gradually narrowed with increasing MTS size. In contrast, PC-10 MTS developed in the physiological oxygen environment were more resistant to DXR than those in air; the differences were again most pronounced in 2 week old MTS. There were little differences in cell kill effects of DDP, irrespective of cells being in monolayer or in MTS and growing in air or in physiological oxygen environment. These observations are consistent with the interpretation that cells in PC-6 MTS are scarcely affected by the physiological oxygen environment but easily affected by DXR, whereas cells in PC-10 MTS responded vice versa.

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“…1 The positive inoculum effect shown in DXR-induced tumor cell kill resulted from lessened cellular accumulation of the drug at high cell densities rather than drug inactivation. 5,6 This phenomenon (posi tive inoculum effect) was originally demonstrated in certain antimicrobial antibiotics of which the inhibitory concentrations in vitro were influenced by the inoculum size of some microbial organisms. 7,8 In experimental animal tumor systems, a remarkable therapeutic synergism was observed in the administration of DXR in combination with CDDP against advanced P388 leukemia and Ridgway osteogenic sarcoma9 as well as Sarcoma 180.10 Combination chemotherapy of these two drugs had marked therapeutic potentiation against ovarian carcinoma and other cancer in man.11 -13 We hypothesized that if DXR is less active at high tumor cell densities and the antitumor effect of CDDP is not influenced by cell density, the proper sequence of administration should be CDDP first followed by DXR, rather than simultaneous exposure or reversed order of the combination.…”

Section: Introductionmentioning

confidence: 98%

Antitumor Efficacy of Doxorubicin in Combination with Cisplatin on Human Lymphoma Cells at Various Cell Densities in vitro.

1991

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Abstract.The influence of tumor cell density on the antitumor effect of doxorubicin (DXR) in combination with cisplatin (CDDP) was studied in vitro using DND-39A lymphoma cells. DXR was progressively less effective on colony formation inhibition when cell density was increased from 105 to 108 viable cells/ml (positive inoculum effect), whereas the effect of CDDP was not influenced by cell densities. At a density of 105 cells/ml, inhibition of colony formation was virtually identical irrespective of cells being exposed to DXR and CDDP either simultaneously or sequentially. When cell density was increased to 107 and 108 cells/ml, sequential exposure to CDDP followed by DXR was more active than simultaneous or reversed order of exposure to the two drugs. These results indicate that for DXR-CDDP combination chemo therapy against the cells at high density, the proper sequence of the treatment should be the administra tion of CDDP followed by DXR, rather than simultaneous or reversed order of exposure. Inoculum effect may be an additional determinant for the rational development of combination chemotherapy.

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Effects of Doxorubicin and Cisplatin on Multicellular Tumor Spheroids from Human Lung Cancer

Cited by 16 publications

References 11 publications

Docetaxel suppresses invasiveness of head and neck cancer cells in vitro

Docetaxel suppresses invasiveness of head and neck cancer cells in vitro

Effects of Physiological Oxygen Environment on Drug-Induced Cell Lethality of Multicellular Tumor Spheroids from Human Lung Cancer

Antitumor Efficacy of Doxorubicin in Combination with Cisplatin on Human Lymphoma Cells at Various Cell Densities in vitro.

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