Modulation of chemotherapy resistance in regional therapy: a novel therapeutic approach to advanced extremity melanoma using intra-arterial temozolomide in combination with systemic <i>O</i>6-benzylguanine

Ueno, Takayoshi; Ko, Sae Hee; Grubbs, Elizabeth G.; Yoshimoto, Yasunori; Augustine, C.; Abdel-Wahab, Zeinab; Cheng, Tsung-Yen; Abdel‐Wahab, Omar; Pruitt, Scott K.; Friedman, Henry S.; Tyler, Douglas S.

doi:10.1158/1535-7163.mct-05-0098

Cited by 41 publications

(30 citation statements)

References 33 publications

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“…This pattern was not observed in the six BRaf WT cell lines. In vivo response to sorafenib in combination with melphalan or temozolomide isolated limb infusion The ability of sorafenib to enhance the effects of high-dose regionally infused chemotherapy was examined in our rat xenograft model of extremity melanoma (33,34) using the DM443 cell line, which was moderately sensitive to sorafenib in vitro (Fig. 1A), moderately sensitive to melphalan both in vitro (Fig.…”

Section: Effects Of Sorafenib On In Vitro Response To Temozolomidementioning

confidence: 99%

Sorafenib, a Multikinase Inhibitor, Enhances the Response of Melanoma to Regional Chemotherapy

Augustine

Toshimitsu

Jung

et al. 2010

Molecular Cancer Therapeutics

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Melanoma responds poorly to standard chemotherapy due to its intrinsic chemoresistance. Multiple genetic and molecular defects, including an activating mutation in the BRaf kinase gene, are associated with melanoma, and the resulting alterations in signal transduction pathways regulating proliferation and apoptosis are thought to contribute to its chemoresistance. Sorafenib, a multikinase inhibitor that targets BRaf kinase, is Food and Drug Administration approved for use in advanced renal cell and hepatocellular carcinomas. Although sorafenib has shown little promise as a single agent in melanoma patients, recent clinical trials suggest that, when combined with chemotherapy, it may have more benefit. We evaluated the ability of sorafenib to augment the cytotoxic effects of melphalan, a regional chemotherapeutic agent, and temozolomide, used in systemic and regional treatment of melanoma, on a panel of 24 human melanoma-derived cell lines and in an animal model of melanoma. Marked differences in response to 10 μmol/L sorafenib alone were observed in vitro across cell lines. Response to sorafenib significantly correlated with extracellular signal-regulated kinase (ERK) downregulation and loss of Mcl-1 expression (P < 0.05). Experiments with the mitogen-activated protein kinase/ERK kinase inhibitor U0126 suggest a unique role for ERK downregulation in the observed effects. Sorafenib in combination with melphalan or temozolomide led to significantly improved responses in vitro (P < 0.05). In the animal model of melanoma, sorafenib in combination with regional melphalan or regional temozolomide was more effective than either treatment alone in slowing tumor growth. These results show that sorafenib in combination with chemotherapy provides a novel approach to enhance chemotherapeutic efficacy in the regional treatment of in-transit melanoma.

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Section: Effects Of Sorafenib On In Vitro Response To Temozolomidementioning

confidence: 99%

Sorafenib, a Multikinase Inhibitor, Enhances the Response of Melanoma to Regional Chemotherapy

Augustine

Toshimitsu

Jung

et al. 2010

Molecular Cancer Therapeutics

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“…In the regional chemotherapy setting, systemic toxicity can be minimized, as only the modulator O 6 BG would be given systemically. We have shown previously the effectiveness of this strategy in our xenograft model using DM6 melanoma, where responses to regional temozolomide were markedly improved with the concurrent administration of systemic O 6 BG in the absence of any increased toxicity (25).…”

Section: Discussionmentioning

confidence: 69%

Defining regional infusion treatment strategies for extremity melanoma: comparative analysis of melphalan and temozolomide as regional chemotherapeutic agents

Augustine¹,

Yoo²,

Zipfel³

et al. 2007

Molecular Cancer Therapeutics

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Five different human melanoma xenografts were used in a xenograft model of extremity melanoma to evaluate the variability of tumor response to regionally administered melphalan or temozolomide and to determine if various components of pertinent drug resistance pathways for melphalan [glutathione S-transferase (GST)/glutathione] and temozolomide [O 6 -alkylguanine DNA alkyltranferase (AGT)/mismatch repair (MMR)] could be predictive of tumor response. Xenograft-bearing rats underwent regional isolated limb infusion with either melphalan (90 mg/kg) or temozolomide (2,000 mg/kg). The levels of AGT activity, GST activity, glutathione level, and GST/AGT expression were examined in this group of xenografts and found to be quite heterogeneous. No correlation was identified between melphalan sensitivity and the GST/ glutathione cellular detoxification pathway. In contrast, a strong correlation between the levels of AGT activity and percentage increase in tumor volume on day 30 (r = 0.88) was noted for tumors treated with temozolomide. Regional therapy with temozolomide was more effective when compared with melphalan for the xenograft with the lowest AGT activity, whereas melphalan was more effective than temozolomide in another xenograft that had the highest AGT activity.

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“…S4). While previous attempts to enhance response to TMZ have focused on O26-methylguanine-DNA methyltransferase inhibition [38,39] or cotreatment with trans-sodium crocetinate (an oxygen diffusion-enhancing compound [40]), our results raise the question of whether restoration of c-Cbl activity might more broadly increase sensitivity to TMZ (and potentially other therapeutic agents).…”

Section: Discussionmentioning

confidence: 75%

Cool‐1‐Mediated Inhibition of c‐Cbl Modulates Multiple Critical Properties of Glioblastomas, Including the Ability to Generate Tumors In Vivo

et al. 2014

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We discovered that glioblastoma (GBM) cells use Cool-1/b-pix to inhibit normal activation of the c-Cbl ubiquitin ligase via the redox/Fyn/c-Cbl pathway and that c-Cbl inhibition is critical for GBM cell function. Restoring normal c-Cbl activity by Cool-1 knockdown in vitro reduced GBM cell division, almost eliminated generation of adhesion-independent spheroids, reduced the representation of cells expressing antigens thought to identify tumor initiating cells (TICs), reduced levels of several proteins of critical importance in TIC function (such as Notch-1 and Sox2), and increased sensitivity to BCNU (carmustine) and temozolomide (TMZ). In vivo, Cool-1 knockdown greatly suppressed the ability of GBM cells to generate tumors, an outcome that was c-Cbl dependent. In contrast, Cool-1 knockdown did not reduce division or increase BCNU or TMZ sensitivity in primary glial progenitor cells and Cool-1/c-Cbl complexes were not found in normal brain tissue. Our studies provide the first evidence that Cool-1 may be critical in the biology of human tumors, that suppression of c-Cbl by Cool-1 may be critical for generation of at least a subset of GBMs and offer a novel target that appears to be selectively necessary for TIC function and modulates chemoresistance in GBM cells. Targeting such proteins that inhibit c-Cbl offers potentially attractive opportunities for therapeutic development. STEM CELLS

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Modulation of chemotherapy resistance in regional therapy: a novel therapeutic approach to advanced extremity melanoma using intra-arterial temozolomide in combination with systemic O6-benzylguanine

Cited by 41 publications

References 33 publications

Sorafenib, a Multikinase Inhibitor, Enhances the Response of Melanoma to Regional Chemotherapy

Sorafenib, a Multikinase Inhibitor, Enhances the Response of Melanoma to Regional Chemotherapy

Defining regional infusion treatment strategies for extremity melanoma: comparative analysis of melphalan and temozolomide as regional chemotherapeutic agents

Cool‐1‐Mediated Inhibition of c‐Cbl Modulates Multiple Critical Properties of Glioblastomas, Including the Ability to Generate Tumors In Vivo

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