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PDF file - 259K, Supplementary Figure 1. CD8+ T cell accumulation in the TRAMP prostate is tumor antigen-dependent. Supplementary Figure 2. Widespread disease regression in 2X WBI + TCR-IV treated mice. Supplementary Figure 3. Recovery from radiation-induced lymphopenia in TRAMP mice.

Adoptive immunotherapy has demonstrated efficacy in a subset of clinical and preclinical studies, but the T cells used for therapy often are rendered rapidly nonfunctional in tumor-bearing hosts. Recent evidence indicates that prostate cancer can be susceptible to immunotherapy, but most studies using autochthonous tumor models demonstrate only short-lived T-cell responses in the tolerogenic prostate microenvironment. Here, we assessed the efficacy of sublethal whole-body irradiation (WBI) to enhance the magnitude and duration of adoptively transferred CD8+ T cells in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. We demonstrate that WBI promoted high-level accumulation of granzyme B (GzB, Gzmb)–expressing donor T cells both in lymphoid organs and in the prostate of TRAMP mice. Donor T cells remained responsive to vaccination in irradiated recipients, but a single round of WBI-enhanced adoptive immunotherapy failed to affect significantly the existing disease. Addition of a second round of immunotherapy promoted regression of established disease in half of the treated mice, with no progression observed. Regression was associated with long-term persistence of effector/memory phenotype CD8+ donor cells. Administration of the second round of adoptive immunotherapy led to reacquisition of GzB expression by persistent T cells from the first transfer. These results indicate that WBI conditioning amplifies tumor-specific T cells in the TRAMP prostate and lymphoid tissue, and suggest that the initial treatment alters the tolerogenic microenvironment to increase antitumor activity by a second wave of donor cells. Cancer Immunol Res; 2(8); 777–88. ©2014 AACR.

We previously showed that metabolic activation of the environmental and tobacco smoke constituent dibenzo[a,l]pyrene (DB[a,l]P) to its active fjord region diol epoxide (DB[a,l]PDE) is required to induce DNA damage, mutagenesis, and squamous cell carcinoma (SCC) in the mouse oral cavity. In contrast to procarcinogens, which were employed previously to induce SCC, DB[a,l]PDE does not require metabolic activation to exert its biological effects, and thus, this study was initiated to examine, for the first time, whether black raspberry powder (BRB) inhibits postmetabolic processes, such as DNA damage, mutagenesis, and tumorigenesis. Prior to long-term chemoprevention studies, we initially examined the effect of BRB (5% added to AIN-93M diet) on DNA damage in B6C3F1 mice using LC/MS-MS and on mutagenesis in the lacI gene in the mouse oral cavity. We showed that BRB inhibited DB[a,l]PDE-induced DNA damage (P < 0.05) and mutagenesis (P = 0.053) in the oral cavity. Tumor incidence in the oral cavity (oral mucosa and tongue) of mice fed diet containing 5% BRB was significantly (P < 0.05) reduced from 93% to 66%. Specifically, the incidence of benign tumor was significantly (P < 0.001) reduced from 90% to 31% (62% to 28% in the oral cavity and 28% to 2% in the tongue), a nonsignificant reduction of malignant tumors from 52% to 45%. Our preclinical findings demonstrate for the first time that the chemopreventive efficacy of BRB can be extended to direct-acting carcinogens that do not require phase I enzymes and is not just limited to procarcinogens. Cancer Prev Res; 11(3); 157–64. ©2017 AACR.

Purpose and Experimental Design: Anaplastic thyroid cancer (ATC) comprises approximately 2% of all thyroid cancers, and its median survival rate remains poor. It is responsible for more than one third of thyroid cancer–related deaths. ATC is frequently resistant to conventional therapy, and NFκB signaling has been proposed to be a feature of the disease. We aimed to assess the activity of the antimalaria drug quinacrine known to target NFκB signaling in combination with the clinically relevant kinase inhibitor sorafenib in ATC cells. The presence of NFκB-p65/RELA and its target MCL1 was demonstrated in ATC by meta-data gene set enrichment analysis and IHC. We assessed the responses of a panel of human ATC cell lines to quinacrine and sorafenib in vitro and in vivo. Results: We detected increased expression of NFκB-p65/RELA and MCL1 in the nucleus of a subset of ATC compared with non-neoplastic thyroid. ATC cells were found to respond with additive/synergistic tumor cell killing to the combination of sorafenib plus quinacrine in vitro, and the drug combination improves survival of immunodeficient mice injected orthotopically with ATC cells as compared with mice administered either compound alone or doxorubicin. We also demonstrate that the combination of sorafenib and quinacrine is well tolerated in mice. At the molecular level, quinacrine and sorafenib inhibited expression of prosurvival MCL1, pSTAT3, and dampened NFκB signaling. Conclusions: The combination of quinacrine and sorafenib targets emerging molecular hallmarks of ATC and shows promising results in clinically relevant models for the disease. Further testing of sorafenib plus quinacrine can be conducted in ATC patients. Clin Cancer Res; 22(24); 6192–203. ©2016 AACR.

We have established a clinically relevant murine model to reveal tumor-induced immunotoerance in hepatocellular carcinoma (HCC). Critical factors are targeted to develop immune-based therapies for HCC control. Intrasplenic (ISPL) inoculation of oncogenic hepatocytes and intraperitoneal (IP) injection of carbon tetrachloride (CCl4) are combined to induce progressive HCCs in fibrotic livers of immunocompetent mice. We characterize the features of this model, examine tumor-antigen-specific (TAS) immunity during tumor initiation and progression, and identify the critical factors in tumor-induced immune tolerance. The established murine model recapitulates human HCC and reflects its typical features. TAS CD8+ T cells initially maintain a naive phenotype and function in early-stage tumor-bearing mice, then become profound exhaustion with the tumor progression to the advanced stage. The deep immunosuppression is associated with the significant upregulation of Programmed cell death protein 1(PD-1), Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the increase of Tregs. While the changes in Tregs and PD-1 are systemic, they are particularly pronounced in the tumor microenvironment. Sunitinib-mediated reduction of Treg together with antibody-mediated blockade of PD-1 synergistically suppress tumor growth and activate anti-tumor immunity. Our data provide evidence that oncogenic hepatocytes escape immune surveillance during tumor initiation via immune ignorance, while later-stage established HCCs evade immune destruction via tumor-induced immunotolerance. Synergy of sunitinib and anti-PD-1 Ab generates favorable effect on suppressing tumor growth and activating anti-tumor immunity. This combinational strategy has high translational potential in HCC treatment. Citation Format: Dai Liu, Guangfu Li, Timothy Cooper, Eric Kimchi, Xiaoqiang Qi, Ningfei Li, Don Rockey, Todd Schell, Kevin Staveley-O’Carroll. Development of a successful combination therapy for hepatocellular cancer by targeting Treg and PD-1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4004.

Despite the identification of several preventive agents and strategies, prevention of lung cancer, especially in smokers who are at high risk, is still largely unattained. 1,4-Phenylenebis(methylene)selenocyanate (p-XSC) has been shown to inhibit tobacco carcinogen NNK induced lung cancer development in several animal models. It metabolizes through the formation of active bis-selenol (p-XSeH) along with the release of poisonous hydrogen cyanide (HCN). Nevertheless, the HCN released upon metabolism of p-XSC to form active metabolite p-XSeH, pose a serious challenge its clinical use in a chemopreventive set up where a continuous intake is required for healthy individuals over a longer period of time. Recently, we developed a hybrid agent, p-XS-Asp, linking p-XSe- to commonly used non-steroidal anti-inflammatory drug, aspirin (Asp), which has been shown to be preventive of lung, and colorectal cancer. We hypothesized that p-XS-Asp would cleave in vivo to release the active p-XSeH, not releasing undesired HCN but the aspirin, thus making the compound less toxic and more potent than p-XSC or aspirin alone. Our studies have shown p-XS-Asp to be orally bioavailable and a highly effective lung cancer chemopreventive agent both in vitro and in animal studies. Elemental selenium (Se) analysis of plasma, lung, and liver tissue in orally fed mice showed that the level of Se significantly higher for p-XS-Asp than p-XSC, denoting a better bioavailability profile for p-XS-Asp. Dietary p-XS-Asp inhibited both O-6 methyl guanine and pyridoxobutyl (pob) DNA adducts, in lung and liver of A/J mice, more effectively than p-XSC. Particularly, in the lung, the inhibition of O-6 methyl guanine adducts, which are critical for A/J mouse lung tumor development, were more than 2 times higher than p-XSC. In a NNK-induced lung cancer A/J mouse model, p-XS-Asp at doses of 15 ppm and 7.5 ppm Se, showed a significantly marked decrease in percentage of lung tumor incidence of 50% and 87%, as compared to p-XSC (79% and 100%), respectively; NNK-control showed an 100% tumor incidence. In addition, the multiplicity for p-XS-Asp was 0.87 and 1.93 tumors/mouse as compared with NNK-control (11.53 tumors/mouse) and p-XSC (1.66 and 4.10 tumors/mouse, respectively) at the two doses tested. Notably, blood and tissue analyses showed no signs of systemic toxicity for the p-XS-Asp fed group. In conclusion, p-XS-Asp, is less toxic and more effective chemopreventive agent than p-XSC and is a promising candidate to future clinical evaluation. Citation Format: Daniel Plano, Cesar Aliaga, Manoj K. Pandey, Arunangshu Das, Timothy K. Cooper, Shantu Amin, Arun K. Sharma. Pre-clinical chemopreventive efficacy of a novel hybrid p-XSC-aspirin compound in a NNK-induced A/J mouse lung cancer model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2139. doi:10.1158/1538-7445.AM2014-2139

Adoptive T cell transfer following whole body irradiation (WBI) can induce dramatic tumor regression in a subset of metastatic melanoma patients. We previously found that this approach also eliminates established autochthonous SV40 T-antigen induced murine brain tumors. However, the broader utility of this immunotherapy approach has not been systematically evaluated in solid tumors of different tissue origin. Here, we assessed the efficacy of applying WBI with adoptive T cell transfer to an SV40 T-antigen driven murine model of prostate cancer (TRAMP) previously shown to rapidly tolerize tumor-specific CD8+ T cells. TRAMP mice bearing established prostate tumors were treated with 475cGy WBI followed by adoptive transfer of T-antigen-specific T cell receptor transgenic CD8+ T cells. Accumulation, phenotype and function of the transferred T cells were monitored by flow cytometry, while therapeutic impact on mouse prostate tumors was assessed by histological scoring. Transferred T cells proliferated in both irradiated and non-irradiated TRAMP mice, but accumulated to significantly higher levels and persisted longer in the secondary lymphoid organs and prostate of irradiated mice. WBI also significantly increased the proportion of T cells that produced the effector molecule granzyme B. Prostate-infiltrating T cells in both treatment groups exhibited an effector differentiated phenotype, although neither developed a significant population of IFNγ-producing cells. Gross observations revealed that the urogenital tract in irradiated TRAMP mice was significantly smaller than that of non-irradiated mice two weeks after transfer, corresponding with a modest but statistically significant drop in pathological score. By three weeks after transfer, when prostate-infiltrating T cells had dramatically contracted in irradiated TRAMP mice, cumulative histological scores were generally equivalent although only mice in the non-irradiated treatment group had progressed to adenocarcinoma. Our results suggest that the addition of irradiation extends the persistence of functional tumor-specific T cells in the highly tolerogenic microenvironment of the TRAMP prostate. T cell accumulation was associated with a short-term delay in progression of established tumors. Citation Format: Lindsay Ward-Kavanagh, Timothy Cooper, Todd D. Schell. Whole body irradiation extends the duration of antitumor immunity toward established prostate tumors by adoptively transferred CD8+ T cells in TRAMP mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3960. doi:10.1158/1538-7445.AM2013-3960

In our previous proteomic study aimed at developing biomarkers for early detection of lung cancer, we identified several proteins that were differentially expressed in lung adenocarcinoma in A/J mice treated with the tobacco-specific nitrosamine NNK and were further modulated by the synthetic selenium chemopreventive agent 1,4-phenylenebis(methylene)selenocyanate (p-XSC). Unfortunately, many potential biomarkers described in previous reports, including our own, are based on comparative analysis between normal and end-stage lung tumors, and thus, can be considered as a consequence of tumor development rather than a cause of cancer induction. Therefore, in the present study we determined the effect of p-XSC and the naturally occurring chemopreventive agent myo-inositol (MI) on protein profiling during different stages of NNK-induced lung tumorigenesis; we used the proteomic approach isobaric Tags for Relative and Absolute Quantitation (iTRAQ). Four groups of mice were included in this study: vehicle, NNK, NNK+p-XSC, and NNK+MI; ten mice were sacrificed at 3 and 9 weeks after the first dose of NNK and additional mice will be sacrificed after 18, 24, and 31 weeks. Histopathology of the lungs showed airway and alveolar epithelial hyperplasia in all groups after 3 and 9 weeks, as well as airway epithelial atypia; however, no clear difference was observed. Equal amounts of total lung protein from five-mice/group were pooled and labeled with one of the isobaric tags 113-119, or 121. Mass spectrometry analysis led to identification of 790 proteins. After 3 and 9 weeks, 11 and 13 proteins, respectively, were significantly modulated in the lungs of mice treated with NNK vs. vehicle-treated mice; of these proteins, filamin-A was down-regulated, while clathrin heavy chain 1 was up-regulated after 3 and 9 weeks in NNK-treated mice; administration of either p-XSC or MI in NNK-treated mice had no apparent affect. After 3 weeks, the 60S ribosomal protein L3 was significantly down-regulated in mice treated with NNK alone, but was up-regulated in mice treated with NNK+p-XSC or MI; after 9 weeks no apparent change was associated with this protein for all groups. After 3 and 9 weeks, using immunoblot analysis, NNK had no apparent effect on 14-3-3 σ protein expression; however, it was increased in lungs of mice treated with NNK+p-XSC and not NNK+MI. The results of this study show that certain proteins in the lung are modulated after 3 and 9 weeks of NNK administration; the impact of p-XSC on NNK-induced protein alteration appears to vary from that observed with MI. Further validation of the proteins identified in this study and proteomic analysis after 18, 24, and 31 weeks of the bioassay will provide better insight into the selection of candidate protein biomarkers for lung cancer development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1852. doi:10.1158/1538-7445.AM2011-1852

Our laboratories are interested in testing the value of combining omega-3 fatty acids and antiestrogens as a safe and effective chemopreventive strategy for breast cancer. We have shown that a fish oil rich diet (FO) (17% FO + 3% corn oil [CO]) enhances the chemopreventive action of Tamoxifen (Tam) in a prepubertal model of N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinogenesis (A. Manni, et al., Cancer Prev Res 3:322, 2010). To gain insight into mechanisms of prevention and the importance of different ratios of n-3:n-6 fatty acids in inhibiting carcinogenesis, we tested the effects of two FO rich diets (17% FO + 3% CO and 10% FO + 10% CO) individually and in combination with Tam on the histologic progression of preneoplastic lesions, indices of proliferation and apoptosis, as well as expression of multiple mammary gland specific and systemic biomarkers of oxidative stress in carcinogen treated rats. Following MNU administration at 21 days of age, separate groups of rats within each experimental arm were sacrificed 24 hours, 21 days, 28 days and 35 days prior to the development of palpable tumors. Increasing the amount of FO in the diet progressively increased the n-3:n-6 ratio in the plasma from 0.13 (20% CO) to 0.38 (10% FO) and 0.96 (17% FO). Although the FO rich diets significantly reduced Ki67 expression in hyperplastic lesions in a dose-dependent fashion (17% FO > 10% FO), neither the diets nor Tam decreased the development of preneoplastic lesions indicating that the inhibitory effect on carcinogenesis results from blocking the transition from hyperplasia to adenocarcinoma, consistent with our recent published study. Dietary FO and/or Tam did not have major effects on systemic oxidative stress biomarkers (plasma protein carbonyls and blood protein bound GSH) or mammary specific biomarkers of oxidative stress, based on oxidative damage to DNA measured as 8-hydroxy-2’-deoxyguanosine (8-OH-dG) and lipid peroxidation assessed as thiobarbituric-acid reactive substances (TBARS). On the other hand, tissue levels of 8-isoprostanes, prostaglandin-like compounds formed by non-enzymatic oxidation of arachidonic acid in the cell membrane, were markedly reduced by both FO rich diets at all time points (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5571. doi:10.1158/1538-7445.AM2011-5571

There are currently no known effective regiments able to prevent the development of estrogen-receptor (ER) negative breast cancer in humans. We hypothesize that ER, frequently upregulated in preneoplastic mammary lesions, may contribute to the development of hormone-independent tumors through crosstalk with multiple cellular oncogenic pathways. Therefore, a multi-targeted approach is likely to be necessary to prevent ER negative tumors. In our previous study, we tested this hypothesis in CD rats and we showed that omega-3 rich fish oil (FO) potentiated the suppressive effect of Tamoxifen (Tam) on mammary carcinogenesis (A. Manni, et al. Cancer Prev Res 3:322, 2010). In the present investigations, we tested this hypothesis in polyoma middle T transgenic mice, since in this experimental system the development of ER negative tumors is preceded by preneoplastic lesions overexpressing functional ER, as evidenced by the concomitant upregulation of progesterone receptors which are products of estrogen action. Administration of increasing concentrations of Tam (1 ppm, 10 ppm, and 100 ppm) admixed with 20% corn oil (CO) modified AIN-76A diet, starting at 3 weeks of age, significantly delayed mammary carcinogenesis, inhibited tumor multiplicity by ∼50%, tumor volume by ∼90%, and tumor weight by ∼70% in a dose dependent fashion. At termination (week 12), however, tumor incidence was nearly 100% in all experimental groups. When Tam treatment was started after tumors had developed, no inhibition of tumor growth was observed, a finding consistent with the absence of ER in invasive adenocarcinomas in this experimental model. Administration of increasing concentrations of FO in the diet (5% FO + 15% CO; 10% FO + 10% CO, 17% FO + 3% CO) started at 3 weeks of age did not affect any of the tumor parameters compared to the control 20% CO diet. Combined administration of suboptimal (1 ppm) and optimal (100 ppm) doses of Tam with 17% FO and 10% FO respectively, delayed carcinogenesis and suppressed tumor multiplicity and volume to the same extent as observed with Tam alone. Therefore, the results indicate that, under these experimental conditions, FO failed to potentiate the chemopreventive action of Tam. Our results, however, provide support for the role of ER expression by the preneoplastic lesions in the development of hormone independent tumors and, consequently, for the importance of including ER targeting in combined chemoprevention strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3710. doi:10.1158/1538-7445.AM2011-3710

Ovarian cancer ranks second among gynecologic cancers, and it is the fifth leading cause of cancer deaths among women; 13,850 deaths are expected in 2010. There is usually no obvious symptoms of early stage ovarian cancer; therefore only 15% of ovarian cancers are diagnosed in the localized stage, and the five-year survival rate for ovarian cancer patients is 46%. A positive relation of mucinous ovarian tumors to tobacco smoking had been reported; furthermore, an association was shown between mucinous ovarian cancer with ex-smokers as well. The mechanisms that can account for the role of tobacco smoking on this disease remain unknown. Currently, there is no preclinical animal model that can accurately reflect the ovarian cancer resulting from chronic exposure to chemical carcinogens present in cigarette smoke. A previous report showed that dibenzo[a,l]pyrene (DB[a,l]P) can induce ovarian cancer in mice. Therefore, in this study we examined the carcinogenicity and DNA adducts formation in the ovary of mice treated with DB[a,l]P. In carcinogenesis study, ovarian tumors in B6C3F1 mice were induced by administering DB[a,l]P into the oral cavity of mice. Several groups of B6C3F1 mice (20/group) received various doses of DB[a,l]P (24, 12, 6, and 3 nmol/mouse), and additional groups received DMSO 3 times a week for 38 weeks or were left untreated as controls. Mice were sacrificed 4 weeks after the last carcinogen administration. A short-term bioassay was also conducted to detect and quantify DNA-adducts induced by DB[a,l]P as a function of time in the ovary; mice were administered orally (24 nmol) 3 times a week for 5 weeks. Ovaries were removed from mice 48 h, 1, 2 and 4 weeks after the last dose. DNA were isolated and hydrolyzed enzymatically, and the DB[a,l]PDE-DNA adducts were analyzed by our newly developed LC-MS/MS method. At the dose of 6 nmol in carcinogenesis study, we observed the highest total ovarian tumor incidence (79%), but the incidence of malignancy was only 15%. However, at the dose of 12 nmol, the total tumor incidence was 75%, and the incidence of malignant granulosa cell tumor was 65%. In addition to ovarian tumors, we also observed lesions in sites distal from the ovaries including the skin, mammary, lung, and oral tissues at the dose of 24 nmol, which were rare in other dosing groups. Treatment of DB[a,l]P in mice resulted in the formation of (−)-anti-cis-DB[a,l]PDE-dA and (−)-anti-trans-DB[a,l]PDE-dA adducts, which were 1.6 and 3.1 fmol/µg DNA respectively in ovaries of mice within 48 hours, and the level of adducts decreased dramatically over a week. Our results indicated that DB[a,l]P can be activated to form (−)-anti-DB[a,l]PDE; the latter may account for DB[a,l]P-induced ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1333. doi:10.1158/1538-7445.AM2011-1333

The annual incidence of cancer of the oral cavity and pharynx in the US is about 30,000 cases, similar to that for leukemia and pancreas, and resulting in a 5 yr survival rate of about 50%. Current models utilizing 4-nitroquinoline-N-oxide in rats and mice or 7,12-dimethylbenzanthracene in the hamster cheek pouch, suffer from relevancy of these synthetic carcinogens and/or the target site. One 2-year feeding study reported that dietary administration of the tobacco smoke carcinogen, benzo(a)pyrene (BaP) leads to tumors at several sites including tongue, but only at very high doses, and mainly in forestomach (Culp, S.J., et al., Carcinogenesis, 9, 117-124, 1998). Here as a potential new model, we investigated whether the more powerful tobacco smoke carcinogen, dibenzo[a,l]pyrene (DB[a,l]P) is mutagenic and carcinogenic in the oral cavity of the B6C3F1 lacI and B6C3F1 mouse resp. upon topical application. Four groups of B6C3F1 lacI mice (6/group) received DB[a,l]P (12, 6, and 3 nmol) or vehicle 3x per week. B6C3F1 mice (20/group) received the same treatment, with an additional 24 nmol group. At 38 weeks the lacI mice were euthanized and DNA was isolated from tongue and upper oral mucosa. For the 12 nmol dose group, the mutant fraction (MF) in the cII gene in upper mucosa and tongue increased about 2-fold relative to that in vehicle-alone (5.2 +/- 0.8 and 4.6 +/- 1.2 vs 2.7 +/- 1.3 and 2.6 +/- 1.2) resp. in units of mutants/105 pfu. The increases were statistically significant (ρ = 0.023 and 0.016) for upper mucosa and tongue resp. The MF's at lower doses were non-significantly elevated. The mutational profile in the DB[a,l]P-induced mutants was compared with that induced by BaP in upper mucosa. BaP was previously shown to be mutagenic in many tissues including oral tissues when administered by gavage (Guttenplan, J.B, et al., Mutation Res., 559,199-210, 2004). Only 4% of BaP-induced mutations were at AT base pairs vs. 31% for DB[a,l]P; consistent with a report of the comparative mutational profile of BaP and DB[a,l]P in lung (Leavitt, S.A., et al., Mutagenesis 23, 445-450, 2008). The fraction of mutations at AT base pairs for DB[a,l]P is very similar to that observed in p53 mutations in the human oral cavity. One yr after the start of treatments, B6C3F1 mice were euthanized and oral squamous cell carcinomas (OSCC) were found in 31% of the high-dose group. Tumors were located in several sites in the oral cavity, although not in tongue. Immunohistochemical analyses revealed that p53 protein was overexpressed in malignant tissues, but not controls. The facts that DB[a,l]P induces mutations and tumors in the oral cavity, and has a mutational profile in oral tissue similar to that found in p53 in human OSCC, indicate DB[a,l]P administration to the mouse oral cavity will likely provide the basis for a new and more relevant model for cancer of the oral cavity than existing models. Supported by NCI grant no. R01 CA 100924 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1968.