Sensitization of Cancer Cells Treated With Cytotoxic Drugs to Fas-Mediated Cytotoxicity

Micheau, Olivier; Solary, Éric; Hammann, Arlette; Martin, François; Dimanche‐Boitrel, Marie‐Thérèse

doi:10.1093/jnci/89.11.783

Cited by 260 publications

(187 citation statements)

References 36 publications

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“…Several chemotherapeutic agents have also been shown to mediate cell death via the Fas/FasL pathway. [30][31][32][33] In the present study, intratumor Ad.mIL-12 gene therapy upregulated the expression of both Fas and FasL in the treated and untreated tumors (Table 2). This upregulation was specific for IL-12 as intratumor injection of Ad.b-gal had no effect ( Figure 7, Table 2).…”

Section: Discussionsupporting

confidence: 53%

Intratumor murine interleukin-12 gene therapy suppressed the growth of local and distant Ewing's sarcoma

et al. 2006

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We evaluated the effect of interleukin-12 (IL-12) gene therapy using an Ewing's sarcoma animal model in T-cell-deficient nude mice. Subcutaneous injection of TC71 cells resulted in tumor development by day 5. Mice were treated with a single intratumor injection of adenovirus b-galactosidase (Ad.b-gal) or adenovirus murine IL-12 (Ad.mIL-12) (2 Â 10 9 PFU) and killed 1-7 days later. Reverse transcriptase-polymerase chain reaction analysis of tumor tissue demonstrated peak expression of IL-12 p35 and p40 at 48 h, which persisted up to 7 days. For in vivo therapy, mice received intratumor Ad.b-gal or Ad.mIL-12 twice weekly for 2.5 weeks starting on day 6. Ad.mIL-12-treated tumors were significantly smaller (median volume, 19.7 mm 3 ; range, 3.41-159.5 mm 3 ) than Ad.b-gal-treated tumors (median volume, 3214.9 mm 3 ; range 1679.9-5909.8 mm 3 , Po0.003) on day 31. The weight of Ad.mIL-12-treated tumors was also lighter than the Ad.b-gal-treated tumors (median, 2 mg; range, 1-5 mg versus median, 1960 mg; range 1640-5230 mg, Po0.01). Ad.mIL-12 therapy significantly prolonged the survival time and also inhibited the growth of an untreated tumor on the contralateral side. Immunohistochemistry analysis of the IL-12-treated tumors demonstrated IL-12 expression with increased Fas, Fas ligand and tumor cell apoptosis. CD31 and vascular endothelial growth factor expression were decreased. These data suggest that IL-12 gene therapy may be useful in the treatment of Ewing's sarcoma.

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Section: Discussionsupporting

confidence: 53%

Intratumor murine interleukin-12 gene therapy suppressed the growth of local and distant Ewing's sarcoma

et al. 2006

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“…5,6 Our previous investigations have indicated that Fas expression in OS cells inversely correlates with their metastatic potential. Cells with high Fas expression do not form lung metastases following i.v.…”

Section: Abstract: Fas; Lung Environment; Toxicitymentioning

confidence: 99%

Aerosol gemcitabine inhibits the growth of primary osteosarcoma and osteosarcoma lung metastases

Koshkina

Kleinerman

2005

Intl Journal of Cancer

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Osteosacarcoma (OS) lung metastases are often resistant to chemotherapy. Most anticancer drugs are administered systemically. In many cases this is followed by dose-dependent toxicity, which may not allow the achievement of therapeutic levels in lungs to eradicate metastases. We determined the efficacy of gemcitabine (GCB) by administering it directly to the lungs via aerosol and studied the role of the Fas pathway in response to the therapy. We used 2 osteosarcoma lung metastases animal models: human LM7 cells that form lung metastases in mice following intravenous injection and murine LM8 cells, which grows subcutaneously in mice and spontaneously metastasize to the lung. Treatment was initiated when the presence of lung metastases had been established. Aerosol GCB inhibited the growth of lung metastases in mice. Intraperitoneal GCB administration at similar dosage had no effect on lung metastases. Besides its direct effect on lung metastases, aerosol GCB suppressed the growth of subcutaneous LM8 tumor. Histopathological examination of mice receiving aerosol GCB showed no evidence of toxicity. Lungs are distinguished from other tissues by the constitutive expression of FasL. Since exposure of tumor cells to GCB upregulated Fas expression, we hypothesized that the susceptibility of the tumor cells to ligandinduced cell death by resident lung cells may be increased. Therefore, the Fas pathway may contribute to the therapeutic effect of aerosol GCB. ' 2005 Wiley-Liss, Inc. Key words: Fas; lung environment; toxicityThe most common site for metastatic spread of OS is the lungs. Patients with OS lung metastases have a poor prognosis with limited therapeutic options. Metastatic and relapsed disease is often resistant to salvage chemotherapy. Our laboratory's goal is to identify new therapeutic approaches for these patients.GCB has been shown to have limited efficacy in the treatment of advanced sarcomas, including OS, 1 but this may be explained in part because systemic administration of GCB does not achieve therapeutic levels in the lungs. We hypothesized that targeted delivery of GCB to the lungs via aerosol will circumvent this problem, yielding a higher drug concentration in the area of the tumor and offer a unique therapeutic opportunity for patients with lung metastases. Indeed, we previously demonstrated that the intranasal administration of GCB at a dose 8-fold lower than the i.v. dose induced the regression of established OS lung metastases. 2 However, the intranasal delivery of drugs to the lungs in humans is not ideal as the drugs will not reach the peripheral regions of the lungs where metastases often develop.Aerosol delivery can bypass this limitation. The clinical feasibility of aerosol drug delivery has been demonstrated with both 9-nitrocamptothecin and GM-CSF. 3,4 In our study, we investigated the efficacy of aerosol GCB in treating OS lung metastases using 2 OS animal model. Aerosol GCB significantly inhibited the growth of primary tumors and of established lung metastases and also prevented metast...

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“…Most chemotherapeutic agents accomplish this task by inducing apoptosis [10,32] through the induction of a death receptor [35] or by activation of the endogenous mitochondrial death pathway [12,23]. Both apoptotic pathways lead individually or collectively [22] to the release of cytochrome c, the activation of initiator and effector caspases [3,16,26,27,28,38] and, ultimately, to cell shrinkage, pyknosis, and karyorrhexis [21,34].…”

Section: Introductionmentioning

confidence: 99%

Fas Death Pathway in Sarcomas Correlates with Epidermal Growth Factor Transcription

Joyner

Aboulafia

Damron

et al. 2008

Clin Orthop Relat Res

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Modulation of apoptosis may influence sarcoma pathogenesis and/or aggressiveness. The Fas death pathway, mediated by FasL or TGFb, is one of two apoptotic pathways. Recent studies report that EGF can modulate TGFb and/or FasL expression/activity; thus, EGF has the potential to influence activation of the Fas pathway. EGF is not always detectable in mesenchymal tumors; therefore, we hypothesized EGF would define which Fas ligand predominates. We assayed 57 surgically removed human sarcomas for 10 genes involved in the Fas pathway. Skeletal muscle biopsies from eight patients served as controls. Sample transcripts were detected by real-time RT-PCR. We attempted to identify relevant predictor variables. The 57 sarcomas were segregated into two categories defined by EGF mRNA content: (1) 23 tumors with EGF concentrations that approximated muscle EGF transcript levels (high-EGF tumors); and (2) 34 tumors that either lacked EGF mRNA, or whose mRNA levels were very low and frequently undetected by PCR (low-EGF tumors). TGFb1 expression best predicted Fas transcript concentrations in the 34 low-EGF sarcomas, while FasL predicted Fas mRNA levels in the remaining 23 high-EGF sarcomas. The results suggest ligand activity in the Fas death pathway correlates with EGF transcription in sarcomas.

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Sensitization of Cancer Cells Treated With Cytotoxic Drugs to Fas-Mediated Cytotoxicity

Abstract: In addition to their direct cytotoxic effects, chemotherapeutic drugs sensitize tumor cells to Fas-mediated cytotoxicity and Fas-dependent immune clearance. On the basis of these findings, new strategies might be developed to improve the efficacy of these drugs.

Cited by 260 publications

References 36 publications

Intratumor murine interleukin-12 gene therapy suppressed the growth of local and distant Ewing's sarcoma

Intratumor murine interleukin-12 gene therapy suppressed the growth of local and distant Ewing's sarcoma

Aerosol gemcitabine inhibits the growth of primary osteosarcoma and osteosarcoma lung metastases

Fas Death Pathway in Sarcomas Correlates with Epidermal Growth Factor Transcription

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