Therapeutic Synergy Between Irinotecan and 5-Fluorouracil against Human Tumor Xenografts

Azrak, Rami G.; Cao, Shousong; Slocum, Harry K.; Tóth, Károly; Durrani, Farukh A.; Yin, Ming; Pendyala, Lakshmi; Zhang, Wanghai; McLeod, Howard L.; Rustum, Youcef M.

doi:10.1158/1078-0432.ccr-0913-3

Cited by 82 publications

(68 citation statements)

References 16 publications

(11 reference statements)

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“…Briefly, no significant difference (p<0.05) in expression levels of those investigated markers was associated with the enhanced therapeutic efficacy of irinotecan except decreased expressions of ATP binding cassette transporters (ABCC1 and ABCG2, efflux pumps of SN-38 the active metabolite of irinotecan) and SN-38 resistant gene developmentally regulated GTP binding protein 1 (DRG1). In addition, poorly-differentiated tumors with slower doubling time (FaDu) seemed to be more sensitive to the combination therapies involving irinotecan [20]. In attempt to understand the mechanism associated with the observed synergy, the plasma and intratumoral pharmacokinetic parameters representing changes in total Se due to MSC supplementation were measured.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy of increasing the therapeutic index of irinotecan, plasma and tissue selenium concentrations is methylselenocysteine dose dependent

Azrak

Cao

Pendyala

et al. 2007

Biochemical Pharmacology

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This study was designed to understand the basis for the efficacy of methylselenocysteine (MSC) in increasing the therapeutic index of irinotecan against human tumor xenografts. Nude mice bearing human FaDu and A253 tumors were treated orally with different doses of MSC and irinotecan. Plasma, tumor and normal tissue samples were collected at different times after MSC treatments and were analyzed for selenium (Se) concentration using electrothermal atomic absorption spectrophotometry. MSC is highly effective in modulating the therapeutic index of irinotecan in the treatment of human squamous cells carcinoma of the head and neck xenografts (FaDu and A253). Enhanced irinotecan efficacy was greater in FaDu tumors (100% CR) than in A253 tumors (60% CR), and depended on MSC dose with a minimum effective dose of 0.01 mg/d x 28. The highest plasma Se concentration was achieved 1 h after a single dose and 28 d after daily treatments of MSC. The ability of FaDu tumors to retain Se was significantly better than A253 tumors, and the highest Se concentration in normal tissue was achieved in the liver. Peak plasma and tissue Se concentrations were functions of the dose and duration of MSC treatment. The MSC-dependent increase in Se level in normal tissues may contribute to the protective effect against irinotecan toxicity observed in those tissues. Intratumoral total Se concentration was not found to be predictive of the combination therapy response rates. There is a critical need to develop a method to measure the active metabolite of MSC, rather than total Se.

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Section: Discussionmentioning

confidence: 99%

“…Previously, Azrak et al [20] characterized untreated controls of A253 and FaDu human xenografts of the head and neck squamous cell carcinomas (HNSCC) using immunohistochemistry. A253 tumors are well-differentiated with an average doubling time of 3.25 days.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of increasing the therapeutic index of irinotecan, plasma and tissue selenium concentrations is methylselenocysteine dose dependent

Azrak

Cao

Pendyala

et al. 2007

Biochemical Pharmacology

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“…Synergistic interactions of anticancer drugs have been reported in studies of tumor cell lines (2 -4), animal models (5), and cancer patients (6). Such interactions include, but are not limited to, the combination of discodermolide and paclitaxel (2), capsicum and green tea concentrate (4), gemcitabine and docetaxel (6), docosahexaenoic acid (DHA) and paclitaxel (7,8), and irinotecan and 5-fluorouracil (5).…”

Section: Introductionmentioning

confidence: 99%

Clioquinol and docosahexaenoic acid act synergistically to kill tumor cells

Ding

Liu

Vaught

et al. 2006

Molecular Cancer Therapeutics

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Clioquinol, an 8-hydroxyquinoline derivative (5-chloro-7-iodo-8-hydroxyquinoline) with antimicrobial properties, has recently been found to have cytotoxic activity towards human cancer cell lines at concentrations achieved by oral administration. This study was initiated to determine whether clioquinol could potentiate the antitumor effects of two drugs, doxorubicin and docosahexaenoic acid (DHA), believed to act in part via the generation of reactant oxidant species. At low micromolar concentrations, clioquinol had little effect upon cell viability and did not potentiate doxorubicin's cytotoxicity. Clioquinol significantly enhanced DHA's cytotoxic effects, an interaction that was shown to be synergistic by isobolographic analysis. Clioquinol exhibited a synergistic interaction with DHA in reducing nuclear factor-KB activity and inducing apoptosis, and the combination reduced the level of several molecules that promote cell survival, including Akt, p65, and Bcl-2. Interestingly, clioquinol neither induced lipid peroxidation itself nor increased peroxidation brought about by the addition of DHA. However, when cells were pretreated with antioxidant vitamin E, the synergism of clioquinol and DHA was blocked, indicating the essential role of lipid peroxidation for their action. These findings reveal a novel antitumor drug combination that synergistically targets major cell survival signaling pathways.

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“…FOLFIRINOX i.v. dosing was adjusted from clinical dosage in accordance with prior maximum tolerated dose studies (21)(22)(23).…”

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confidence: 99%

Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma

Byrne

Jajja

Schorzman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Poor delivery and systemic toxicity of many cytotoxic agents, such as the recent promising combination chemotherapy regimen of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), restrict their full utility in the treatment of pancreatic cancer. Local delivery of chemotherapies has become possible using iontophoretic devices that are implanted directly onto pancreatic tumors. We have fabricated implantable iontophoretic devices and tested the local iontophoretic delivery of FOLFIRINOX for the treatment of pancreatic cancer in an orthotopic patientderived xenograft model. Iontophoretic delivery of FOLFIRINOX was found to increase tumor exposure by almost an order of magnitude compared with i.v. delivery with substantially lower plasma concentrations. Mice treated for 7 wk with device FOLFIRINOX experienced significantly greater tumor growth inhibition compared with i.v. FOLFIRINOX. A marker of cell proliferation, K i -67, was stained, showing a significant reduction in tumor cell proliferation. These data capitalize on the unique ability of an implantable iontophoretic device to deliver much higher concentrations of drug to the tumor compared with i.v. delivery. Local iontophoretic delivery of cytotoxic agents should be considered for the treatment of patients with unresectable nonmetastatic disease and for patients with the need for palliation of local symptoms, and may be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer.iontophoresis | FOLFIRINOX | pancreatic cancer | device delivery | chemotherapy

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Therapeutic Synergy Between Irinotecan and 5-Fluorouracil against Human Tumor Xenografts

Cited by 82 publications

References 16 publications

Efficacy of increasing the therapeutic index of irinotecan, plasma and tissue selenium concentrations is methylselenocysteine dose dependent

Efficacy of increasing the therapeutic index of irinotecan, plasma and tissue selenium concentrations is methylselenocysteine dose dependent

Clioquinol and docosahexaenoic acid act synergistically to kill tumor cells

Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma

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