Adenovirus-mediated p53 gene therapy has greater efficacy when combined with chemotherapy against human head and neck, ovarian, prostate, and breast cancer

Gurnani, Maya; Lipari, Philip; Dell, Janet; Shu, Bin; Nielsen, Loretta L.

doi:10.1007/s002800050959

Cited by 103 publications

(48 citation statements)

References 22 publications

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“…Recent reports demonstrated that p53 missense mutants markedly reduced DNA binding of wild-type p53 Previous reports have demonstrated that the combination of adenoviral p53 and cisplatin was cooperative in ovarian, breast, lung, pancreatic, prostate, head and neck cancer cells expressing mutant p53. [10][11][12][26][27][28] Furthermore adenoviral p53 might enhance the effect of taxanes in lung and ovarian cancer. 9,10,12,29 Although it appears that p53 is not involved in paclitaxel-dependent apoptosis, 30 it may enhance adenoviral transduction efficiency.…”

Section: Discussionmentioning

confidence: 99%

“…[10][11][12][26][27][28] Furthermore adenoviral p53 might enhance the effect of taxanes in lung and ovarian cancer. 9,10,12,29 Although it appears that p53 is not involved in paclitaxel-dependent apoptosis, 30 it may enhance adenoviral transduction efficiency. 9 In our study, testing a representative number of 14 ovarian cancer cell lines, we observed that adenoviral p53 gene therapy improved paclitaxel and/or carboplatin chemotherapy in cell lines with mutant p53 as well as with wt p53.…”

Section: Discussionmentioning

confidence: 99%

“…8 Gene transfer of a wild-type p53 gene is intended to reverse the loss of normal p53 function and has been demonstrated to reduce proliferation of tumor cells alone or in combination with chemotherapy in vitro and in vivo among different types of tumors, such as breast, 9,10 head and neck, 9,10 prostate, 9,10 pancreas, 11 lung, 12 as well as ovarian cancer. 9,10,13,14 At least three major issues remain unclear when this therapeutic strategy is applied to ovarian cancer: the efficiency of the adenoviral transduction in ovarian cancer cells, the effect of adenoviral p53 on tumor cells with endogenous wild-type p53, the efficacy of the combination of current standard paclitaxel/carboplatin chemotherapy with adenoviral p53 gene transfer, systematically analyzed with regard to the mutational status. In this study, an E1-deleted adenovirus type 5 expressing p53 (ACNp53) was transferred into 14 ovarian cancer cell lines with different p53 mutation status to determine its effect in combination with paclitaxel/carboplatin chemotherapy.…”

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Cooperative effect of adenoviral p53 gene therapy and standard chemotherapy in ovarian cancer cells independent of the endogenous p53 status

et al. 2004

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Clinical adenoviral p53 gene therapy has been shown by us and others to inhibit tumor growth of ovarian cancer with endogenous mutant p53. This study was designed to test the cooperative antitumor effect of standard combination chemotherapy using paclitaxel and carboplatin together with adenoviral p53 gene transfer in the presence of wild-type and mutant p53. Seven ovarian cancer cell lines with mutant p53 and seven ovarian cancer cell lines with wild-type p53 were tested. An E1-deleted adenovirus type 5 expressing p53 (ACNp53) was used for p53 gene transfer. p53 gene transfer at 50% transduction efficiency significantly reduced IC 50 of carboplatin chemotherapy up to 49-fold, of paclitaxel chemotherapy up to six-fold, and of paclitaxel/carboplatin chemotherapy up to 19-fold in the wild-type p53 cell line OV-MZ-5. Synergism between ACNp53 and chemotherapy calculated by median-effect analysis was found at low drug concentrations in all cell lines independent of the p53 mutational status. In conclusion, adenoviral p53 gene transfer significantly increased the sensitivity of ovarian tumor cells to paclitaxel, to carboplatin and/or to the combination of both.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Cooperative effect of adenoviral p53 gene therapy and standard chemotherapy in ovarian cancer cells independent of the endogenous p53 status

et al. 2004

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“…Moreover, strategies combining adenovirus-mediated wild-type p53 gene transfer with DNA-damaging treatments, such as irradiation and chemotherapeutic agents, have also been explored in glioblastoma, lung, colorectal, ovarian, and head and neck cancers. These combination therapies involving p53 over expression have consistently demonstrated enhanced tumor suppressing activity, relative to single agents [11,12]. Finally, in androgen-independent prostate cancer cells, significant cytotoxicity has been previously reported with over expression of recombinant wild-type p53 using an adenovirus vector (Ad5CMV-P53) [13,14].…”

Section: Introductionmentioning

confidence: 95%

2-Deoxyglucose combined with wild-type p53 overexpression enhances cytotoxicity in human prostate cancer cells via oxidative stress

Ahmad

Abdalla

Aykin-Burns

et al. 2008

Free Radical Biology and Medicine

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Over expression of the tumor suppressor gene, wild type p53 (wtp53), using adenoviral vectors (Adp53) has been suggested to kill cancer cells by hydroperoxide-mediated oxidative stress [1,2] and nutrient distress induced by the glucose analog, 2-deoxyglucose (2DG), has been suggested to enhance tumor cell killing by agents that induce oxidative stress via disrupting hydroperoxide metabolism [3,4]. In the current study clonogenic cell killing of PC-3 and DU-145 human prostate cancer cells (lacking functional p53) mediated by 4 h exposure to 50 plaque forming units (pfus)/ cell of Adp53 (that caused the enforced over expression of wtp53) was significantly enhanced by treatment with 2DG. Accumulation of glutathione disulfide was found to be significantly greater in both cell lines treated with 2DG+Adp53 and both cell lines treated with 2DG+Adp53 showed a ~2-fold increases in dihydroethidine (DHE) and 5-(and-6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate (CDCFH 2 ) oxidation, indicative of increased steady-state levels of O 2 •-and hydroperoxides, respectively. Finally, over expression of catalase or glutathione peroxidase using adenoviral vectors partially, but significantly, protected DU-145 cells from the toxicity induced by 2DG+Adp53 treatment. These results show that treatment of human prostate cancer cells with the combination of 2DG (a nutrient stress) and over expression of the tumor suppressor gene, wtp53, enhances clonogenic cell killing by a mechanism that involves oxidative stress as well as allowing for the speculation that inhibitors of glucose and hydroperoxide metabolism can be used in combination with Adp53 gene therapy to enhance therapeutic responses.

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“…Preclinical data support this theory. 7,10,12 In addition, several reports have suggested that even drugs, which induce apoptosis independent of p53, can synergize with SCH58500 through multiple mechanisms. 12,17 Results from early clinical trials using SCH58500 by itself support optimism for the future of this therapeutic approach to cancer treatment.…”

mentioning

confidence: 99%

Development and validation of sensitive assays to quantitate gene expression after p53 gene therapy and paclitaxel chemotherapy using in vivo dosing in tumor xenograft models

Wen¹,

Xie²,

McDonald³

et al. 2000

Cancer Gene Ther

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SCH58500 ( ACN53 ) is a replication -deficient, type 5 adenovirus ( Ad ) expressing human wild -type p53 tumor suppressor. It is currently undergoing clinical trials as a cancer therapeutic. Many SCH58500 clinical trials incorporate an arm comparing traditional chemotherapy against chemotherapy combined with SCH58500. Paclitaxel was chosen for combination therapy in the preclinical study reported here due to its extensive use as a first -line therapy in ovarian cancer, its synergy with SCH58500 in preclinical cancer models, and its activation of p53 -independent apoptosis, which might result in a``lowered threshold'' for tumor cell death. SCID mice bearing human tumor xenografts were dosed with intratumoral vehicle, control Ad vector, or SCH58500, with or without paclitaxel. Real -time quantitative reverse transcriptase polymerase chain reaction assays were developed and validated to quantitate expression of p53, the p53 downstream effector gene p21, and the apoptosis -related genes, bax, bcl -2, and survivin. Protein expression was confirmed using immunohistochemical assays for p53 and p21. Only tumors injected with SCH58500 had detectable levels of exogenous p53 DNA and mRNA. After SCH58500 treatment, 3 ± 11 ± fold elevations of p21 expression were observed in tumor xenografts containing nonfunctional p53 ( MDA -MB -468, MDA -MB -231, MIAPaCa2, DU -145, and SK -OV -3 ) , but no change in p21 mRNA in wild -type p53 PA -1 tumors. Immunohistochemical assays confirmed induction of p21 protein in MDA -MB -468 and SK -OV -3 cells, but not in PA -1 cells. Ad vector alone or paclitaxel alone had no effect on p21 mRNA levels in most tumors. However, paclitaxel suppressed p21 expression induced by SCH58500 4 -fold in DU -145 and SK -OV -3 tumors. Paclitaxel also affected expression of the housekeeping gene gapdh. There was no consistent pattern to the changes in bax, bcl -2, or survivin after SCH58500 treatment with or without paclitaxel between tumor types, although there were consistent responses within individual tumor lines. The mRNA ratios for bax / bcl -2 and bax / survivin were also not informative across tumor types. Of the genes examined, only p21 gave a predictable response 24 hours after p53 gene therapy and therefore, p21 expression may be useful for confirming SCH58500 activity in human tumor biopsies.

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Adenovirus-mediated p53 gene therapy has greater efficacy when combined with chemotherapy against human head and neck, ovarian, prostate, and breast cancer

Abstract: These results support the combination of p53 gene therapy with chemotherapy in clinical trials.

Cited by 103 publications

References 22 publications

Cooperative effect of adenoviral p53 gene therapy and standard chemotherapy in ovarian cancer cells independent of the endogenous p53 status

Cooperative effect of adenoviral p53 gene therapy and standard chemotherapy in ovarian cancer cells independent of the endogenous p53 status

2-Deoxyglucose combined with wild-type p53 overexpression enhances cytotoxicity in human prostate cancer cells via oxidative stress

Development and validation of sensitive assays to quantitate gene expression after p53 gene therapy and paclitaxel chemotherapy using in vivo dosing in tumor xenograft models

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