| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics, Preclinical Pharmacology |
1 Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; 2 Section of General Thoracic Surgery, Department of Surgery and 3 Department of Pathology, University of Michigan, Ann Arbor, Michigan; 4 Division of Biometrics, University of Medicine and Dentistry of New Jersey School of Public Health, New Brunswick, New Jersey; and 5 Chemoprevention Branch, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Experimental Design: 5-Lox expression in EAC of a rat esophagogastroduodenal anastomosis model and of humans was examined with immunohistochemistry. A chemoprevention study was designed to test whether zileuton and celecoxib could suppress aberrant AA metabolism and esophageal adenocarcinogenesis.
Results: With immunohistochemistry, we found that 5-Lox was overexpressed during esophageal adenocarcinogenesis in our rat model and in humans. In the chemoprevention study, EAC incidence was reduced in a dose-dependent manner from 68.8% (11 of 16) to 44.4% (8 of 18; P > 0.05) and 31.3% (5 of 16; P < 0.05) by 500 and 1,000 ppm zileuton, respectively, and to 33.3% (7 of 21; P < 0.05) and 20% (3 of 15; P < 0.05) by 500 and 1,000 ppm celecoxib, respectively. With isobolographic analysis, zileuton and celecoxib, both at a dose of 500 ppm, had an additive effect by reducing the tumor incidence to 16.7% (3 of 18, P < 0.01). Leukotriene B4 and prostaglandin E2 levels in the esophageal tissues were also significantly reduced by zileuton and celecoxib.
Conclusions: This study clearly demonstrated that 5-Lox and Cox2 play important roles in the development of EAC. Both zileuton and celecoxib had inhibitory effects on esophageal adenocarcinogenesis through inhibition on their respective enzymes of AA metabolism.
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Several lines of evidence suggested an important role of aberrant arachidonic acid (AA) metabolism in human esophageal adenocarcinogenesis. Intake of nonsteroidal anti-inflammatory drugs was associated with a lower risk of EAC (4) , especially for those who overexpressed cyclin D1 (5) . Cyclooxygenase (Cox) 2 was overexpressed in human EAC, and its high expression level was associated with poor clinical prognosis (6) . Gastric acid and bile acids in gastroesophageal refluxate enhanced the expression of Cox2 expression (7 , 8) . As a result, prostaglandin E2 (PGE2) levels were increased in reflux esophagitis and suppressed by antacid therapy (9) . Specific Cox2 inhibitors induced apoptosis in human EAC cell lines and primary esophageal epithelial cells from biopsy samples (10 , 11) . During rat esophageal adenocarcinogenesis, Cox2 was overexpressed and PGE2 was overproduced (8 , 12) . Specific and nonspecific Cox2 inhibitors (sulindac and MF-tricyclic) significantly reduced the incidence of EAC in the rat models (12 , 13) .
Besides the Cox2 pathway, the lipoxygenase pathways are also important in carcinogenesis. The major AA metabolites of the 5-lipoxygenase (5-Lox) pathway, 5(S)-hydroeicosatetraenoic acid, leukotriene B4 (LTB4), and cysteinyl leukotrienes, are known to recruit and activate inflammatory cells, increase vascular permeability, and induce contraction of smooth muscles (14) . 5-Lox knockout mice are more resistant to inflammation and certain inflammation-associated diseases and more susceptible to infections than wild-type mice (15) . Recently, 5-Lox has been found to be overexpressed in many human cancers, such as prostate (16) , pancreatic (17) , colon (18) , bladder (19) , and testicular cancer (20) . In human colon cancer, 5-Lox overexpression was associated with poor clinical prognosis, especially for patients with Dukes’ B stage disease (18) . Inhibition of the 5-Lox pathway had antiproliferative and proapoptotic effects on different cancer cell lines (21) . Chemopreventive effects of chemical compounds targeting enzymes and receptors on the 5-Lox pathway have been demonstrated in animal models of lung, skin, and pancreatic cancer (22, 23, 24, 25, 26) .
Normal esophageal squamous epithelium has limited 5-Lox activity and produces limited amounts of LTB4. However, the levels of LTB4 in human esophageal biopsy samples of reflux esophagitis and CLE increased markedly (27) , and antacid therapy reduced LTB4 levels (9) . In human EAC samples and in a rat model, we found overexpression of leukotriene A4 hydrolase (LTA4H, the rate-limiting enzyme for synthesis of LTB4) and an increased level of LTB4. Bestatin, a LTA4H inhibitor, suppressed LTB4 level and carcinogenesis in our rat model (28) . These results suggest that the 5-Lox pathway of AA metabolism plays an important role in esophageal adenocarcinogenesis. In this study, we examined the expression of 5-Lox in human and rat EAC. Zileuton, a specific 5-Lox inhibitor used clinically for asthma, was used alone or in combination with celecoxib, a specific Cox2 inhibitor, to determine its effect on carcinogenesis in our rat surgical model.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. The rat samples were obtained from a previous study (29)
. Each of the rat tissue sections contained different histology including normal esophagus, esophagitis, CLE, and EAC. Human samples were obtained from paraffin blocks from the pathology archives of the University of Michigan. They were used to construct tissue microarrays using standard techniques (30)
. Institutional review board approval (University of Michigan) was obtained to perform immunohistochemistry using archival tissues.
|
Chemoprevention of EGDA-Induced Esophageal Adenocarcinoma in Rats by Zileuton and Celecoxib.
A short-term experiment (4 weeks after surgery) was designed to find the proper doses of zileuton and celecoxib for EGDA rats. EGDA was performed on 8-week-old male Sprague-Dawley rats (Taconic, Germantown, NY) according to the procedure described previously (29)
, which was approved by the Animal Care and Facilities Committee at Rutgers University (Protocol 94-017). Five EGDA rats were fed with respective AIN93M-based diets containing the test agents (500 or 1,000 ppm zileuton, 500 or 1,000 ppm celecoxib, or 500 ppm zileuton + 500 ppm celecoxib) starting 1 day after EGDA surgery and continuing for 4 weeks. All of the diets were prepared by Research Diets (New Brunswick, NJ). Body weight was monitored once per week throughout the experiment. Food and fluid intake were measured at weeks 1, 2, and 4 after surgery. At each time point, three consecutive days were monitored. Liver and kidney were harvested and examined for possible toxic effects after hematoxylin and eosin staining of tissue sections.
In the long-term chemoprevention experiment (40 weeks after surgery), EGDA rats were randomly assigned to different groups and given the chemopreventive agents in the diet starting 1 day after surgery (Table 2)
. Forty weeks after surgery, the rats were sacrificed, and their esophagi were examined for gross abnormalities. Tumor volume was determined by measuring the height, length, and width of all visible tumors and by using the average of these three measurements as the diameter (volume = 4/3
r3). A small piece of esophageal tissue at the squamocolumnar junction (from the anastomosis line to 5 mm above) was also harvested and stored at –80°C for future analysis of LTB4 and PGE2. The remaining esophageal tissue was fixed in 10% buffered formalin, Swiss rolled, and processed routinely. Histopathological analysis was carried out using the first, tenth, twentieth and thirtieth slides stained with hematoxylin and eosin. Dysplasia was diagnosed by the partial loss of cell polarity and maturation, nuclear atypia, and an increase in mitotic figures. EAC was diagnosed when dysplastic columnar epithelial cells invaded through the basement membrane (31)
.
|
Statistical Considerations and Analysis.
A contingency table 
2 test was performed to analyze the association of 5-Lox immunohistochemical staining intensity with histology in human esophageal tissue samples. The incidence of EAC was analyzed by Fisher’s exact test, and the tumor size was analyzed by Wilcoxon Mann-Whitney test. The dose-response analysis on zileuton and celecoxib was performed with Mantel-Haenszel 2 test. Student’s t test was used for analysis of LTB4 and PGE2.
The combination effect of zileuton and celecoxib on carcinogenesis was assessed using the method of Laska et al. (32) . We took 500 and 1,000 ppm as the doses of zileuton and celecoxib. We assumed that the expected response with zileuton at a dose of 500 ppm and celecoxib at a dose of 500 ppm [g(500 ppm zileuton + 500 ppm celecoxib)] was a monotone, nondecreasing, and continuous function. Synergistic, additive, or antagonistic effects were defined if g(500 ppm zileuton + 500 ppm celecoxib) was greater than, equal to, or less than g(1,000 ppm zileuton) and g(1,000 ppm celecoxib). Here g was defined as the inhibition rate on the tumor incidence in our animal model.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. In the areas of EGDA-induced esophagitis and CLE, 5-Lox was overexpressed in the squamous epithelial cells, especially in the columnar epithelial cells and infiltrating inflammatory cells (Fig. 1B and C)
. In EAC, 5-Lox was further overexpressed in both epithelial cells and infiltrating inflammatory cells (Fig. 1D)
. The esophageal samples from 20 EGDA rats showed the same pattern of 5-Lox expression.
|
). 5-Lox expression was markedly increased in CLE and dysplasia, with most cases positively stained (Fig. 1F and G)
. In EAC, overexpression was obvious in 50% of the cases (28 of 56), with staining intensity at the level of ++ and +++. There were six cases of EAC showing very strong staining of 5-Lox (Fig. 1H
; Table 1
). Positive staining was observed mainly in the cytoplasm. With a contingency table 2 test, there was a significant association between staining intensity and histology (P < 0.0001). The results showed that in both our rat model and human tissue samples, there was a progressive increase in 5-Lox expression during histologic progression to EAC. More importantly, 5-Lox was overexpressed at the stage of CLE, an early stage of esophageal adenocarcinogenesis.
Chemopreventive Effects of Zileuton and Celecoxib.
In the short-term (4 weeks after surgery) dose-finding experiment with five rats in each group, all of the animals survived both surgery and treatment with zileuton or celecoxib. We did not detect a statistically significant difference in food or fluid intake at 1, 2, and 4 weeks after surgery in groups receiving zileuton (500 or 1,000 ppm), celecoxib (500 or 1,000 ppm), or the combination of agents (500 ppm each agent). No significant difference in body weight among all of the groups was observed. No obvious toxicity was observed when the histology of liver and kidney of the five rats from each group was examined.
In the long-term experiment (40 weeks after surgery), 104 of 110 (94.6%) animals survived the surgery and remained healthy until the end of the experiment. During the experiment, these animals were active and healthy. In the early time points (up to 16 weeks after surgery), body weights of the experimental groups (groups II–VII) were slightly lower than those of the nonoperated control (group I), but the difference was not significant (P > 0.05). After 16 weeks, all of the experimental groups had significantly lower body weights than the nonoperated control group (P < 0.05). However, treatment with zileuton and/or celecoxib had no significant effect on body weight as compared with the EGDA group (group II; P > 0.05; Fig. 2
).
|
). This was due to the large variation in tumor sizes even within the same group. It suggested that factors other than 5-Lox and Cox2 may play important roles in tumor growth once a tumor is developed.
|
2 test, we found that zileuton inhibited tumor incidence in a dose-dependent manner (P < 0.05). The chemopreventive effect of celecoxib was slightly stronger than that of zileuton. At the dose of 500 ppm, celecoxib had a significant inhibitory effect on carcinogenesis with a tumor incidence of 33.3% (7 of 21; P < 0.05). At the dose of 1,000 ppm, the incidence of EAC was further significantly reduced to 20% (3 of 15; P < 0.05). Similar to zileuton, celecoxib also inhibited tumor incidence in a dose-dependent manner (P < 0.01; Table 2
).
When zileuton and celecoxib were administered in combination (500 ppm each), the incidence of EAC was dramatically reduced to 16.7% (3 of 18; P < 0.01; Table 2
). To determine the combination effect between zileuton and celecoxib, we used the method of Laska et al. (32)
. At a dose of 1000 ppm, zileuton inhibited tumorigenesis by 54.5% and celecoxib inhibited tumorigenesis by 70.9%, respectively. When both were at doses of 500 ppm, the combination of zileuton and celecoxib inhibited tumorigenesis by 75.7% (Table 2)
. The combination 500 ppm zileuton + 500 ppm celecoxib was only slightly [but not statistically significantly (P > 0.05)] more effective than 1,000 ppm zileuton alone and 1,000 ppm celecoxib alone. It indicated an additive inhibitory effect of 500 ppm zileuton + 500 ppm celecoxib on esophageal adenocarcinogenesis in our animal model.
Effects of Zileuton and Celecoxib on the Levels of Leukotriene B4 and Prostaglandin E2.
Both LTB4 and PGE2 increased dramatically in all of the EGDA rats (group II) as compared with the nonoperated control (group I; P < 0.0001; Table 2
). Treatment with 500 ppm zileuton (group III) or 500 ppm celecoxib (group V) did not significantly reduce the levels of LTB4 (P > 0.05). A dose of 500 ppm zileuton, but not 500 ppm celecoxib, reduced the level of PGE2 (P < 0.05). When the doses were increased to 1,000 ppm, both zileuton and celecoxib were significantly effective in reducing the levels of both LTB4 and PGE2 (P < 0.05). In the combination group (group VII), the levels of both LTB4 and PGE2 were inhibited significantly (P < 0.05).
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
There are two major sources of 5-Lox in the esophagi of humans and EGDA rats: resident or infiltrating inflammatory cells, and epithelial cells (33)
. As shown in Fig. 1
, 5-Lox was expressed not only in inflammatory cells but also in esophageal epithelial cells, in both rat and human samples. This finding was consistent with our observation of 5-Lox expression in human esophageal epithelial cells (HET1A, SEG-1, FLO-1, BIC-1, SKGT4, and BE3) by reverse transcription-polymerase chain reaction and Western blotting (data not shown). As we and others have shown in previous studies (8
, 12
, 28)
, other AA-metabolizing enzymes (such as Cox2 and LTA4H) were also expressed in esophageal epithelial cells of human and rat tissue samples. These findings suggested that, besides inflammatory cells, esophageal epithelial cells actively participated in local inflammation by producing AA metabolites, such as LTB4 and PGE2. In this study, we found overexpression of 5-Lox during esophageal adenocarcinogenesis in both human samples and animal models. 5-Lox was overexpressed at the early stages of carcinogenesis, esophagitis, and CLE (Fig. 1
; Table 1
), similar to the Cox2 expression pattern (12)
. This observation provides a mechanistic rationale for targeting 5-Lox at the early stage of esophageal adenocarcinogenesis to prevent this deadly cancer.
5-Lox metabolites are important mediators of inflammation and inflammation-associated carcinogenesis. Recent studies in cell lines showed that LTB4 stimulated the proliferation of human cancer cells, enhanced oxidative stress, and stimulated cell spreading (34) . Receptors of LTB4 and cysteinyl leukotrienes were overexpressed in some human pancreatic and colon cancers (17 , 18) . Consistent with the proinflammatory and carcinogenic effects of 5-Lox metabolites, 5-Lox inhibitors had chemopreventive effects in several animal models of carcinogenesis. In a carcinogen-induced pancreatic cancer model in hamsters, zileuton (28 mg/day) and a combination of zileuton (28 mg/day) and celecoxib (7 mg/day) significantly inhibited tumor incidence and tumor size (25) . A combination of zileuton and celecoxib also significantly reduced the incidence, number, and size of liver metastases (26) . Similar chemopreventive effects of 5-Lox pathway inhibitors have been demonstrated in carcinogen-induced models of lung (22 , 23) , skin (24) , and oral cancer.6 In the esophagus, we previously demonstrated LTA4H as a chemopreventive target, and a LTA4H inhibitor, bestatin, significantly suppressed carcinogenesis in the rat EGDA model (28) . In the present study, zileuton alone was effective in preventing EAC in the EGDA rats, and the preventive effect was dose dependent.
Consistent with previous results by others and us (12 , 13) using nonspecific or specific Cox inhibitors (sulindac and MF-tricyclic), celecoxib at doses of 500 and 1,000 ppm significantly inhibited esophageal adenocarcinogenesis in our rat EGDA model. With the calculation of nutrient density, we estimated these doses at about 0.13 to 0.26 mg/kcal (35) , similar to the commonly used doses of celecoxib in humans (200–400 mg/day or 0.1–0.2 mg/kcal). With a clinical trial on the chemopreventive effect of celecoxib (200 mg, by mouth, twice a day) in human Barrett’s esophagus patients ongoing (36) , it would be interesting to find out whether the animal study might help dose selection for human studies.
An interesting finding of this study was that zileuton and celecoxib were not only effective alone in inhibiting carcinogenesis in the EGDA rats but also exerted an additive effect when used in combination (each at a dose of 500 ppm). The incidence of EAC was reduced significantly from 68.8% to 16.7% by the combination. Similarly, inhibition of both 5-Lox and Cox pathways was more effective than inhibition of either pathway alone in a lung cancer model (22) . In our study of the hamster oral cancer model, the combination of zileuton and celecoxib was also additive in inhibiting carcinogenesis. We believe targeting both the 5-Lox and Cox2 pathways might be more potent in suppressing inflammation and carcinogenesis in patients at risk for EAC than targeting either one of these pathways alone.
The 5-Lox and Cox2 pathways interact closely. Previous studies have shown that genetic knockout of 5-Lox (37)
or Cox1/Cox2 (38)
resulted in activation of the other pathway. Chemical inhibitors of one pathway may also activate other AA-metabolizing pathways (39)
. In this study, we examined the levels of LTB4 and PGE2 in esophageal epithelial tissues of EGDA rats at 40 weeks after surgery. When zileuton or celecoxib alone was administered to the EGDA rats, the levels of LTB4 and PGE2 decreased concurrently at the high doses, and there was no obvious activation of the other pathway (Table 2)
. It was possible that in this long-term experiment, the levels of LTB4 and PGE2 reflected the extent of inflammation. Thus, the levels of both LTB4 and PGE2 were reduced by 1,000 ppm zileuton or celecoxib, as well as by the combination of these agents at 500 ppm. At 500 ppm, neither agent reduced the levels of LTB4 and PGE2 significantly (except that zileuton reduced the level of PGE2), although celecoxib inhibited EAC formation. The large variations in LTB4 and PGE2 among the samples from different animals hindered our effort to correlate inhibition of carcinogenesis with inhibition of AA metabolism.
It should be noted that zileuton and celecoxib might also inhibit carcinogenesis by mechanisms other than inhibition of AA metabolism. For example, 500 ppm zileuton significantly reduced PGE2 levels, but not LTB4 levels. Carcinogenesis was inhibited slightly, but not significantly. As a hydroxyurea compound, zileuton is an iron chelator (40) . In our animal model of EAC, iron has been shown to promote carcinogenesis by inducing oxidative damage (31) . Cox2-independent anticarcinogenic actions of celecoxib have been well documented in the literature. In a cell culture study, similar levels of apoptosis were observed in Cox2-positive and Cox2-negative epithelial cancer cells after treatment with celecoxib (41) . Genetic up- or down-regulation of Cox2 in a colon cancer cell line significantly altered the effects of celecoxib on cell survival and apoptosis, but not cell cycle arrest (42) . A study is ongoing in our laboratory to test whether zileuton and celecoxib can suppress tumorigenesis in 5-Lox or Cox2 knockout mice. With both the pharmacological and the genetic approaches, we may clarify the roles of 5-Lox and Cox2 in the development of EAC.
In summary, this study clearly demonstrated that 5-Lox and Cox2 played an important role in the development of EAC, and both zileuton and celecoxib prevented esophageal adenocarcinogenesis through inhibition on their respective AA-metabolizing enzymes. Currently, there are two ongoing clinical trials assessing the effectiveness of zileuton in the treatment and prevention of lung cancer.7 New 5-Lox inhibitors and dual Cox/5-Lox inhibitors with more potent anti-inflammatory effects are also under development or in clinical trials (39) . It would be interesting to test whether a combination of a 5-Lox inhibitor and a Cox2 inhibitor might be more effective than a single agent on esophageal adenocarcinogenesis in clinical trials.
|
FOOTNOTES |
|---|
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Xiaoxin Chen, Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854. Phone: 732-445-3400, ext. 259; Fax: 732-445-0687; E-mail: xiaochen{at}rci.rutgers.edu
6 N. Li, S. Sood, S. Wang, M. Fang, P. Wang, Z. Sun, C. S. Yang, and X. Chen. Overexpression of cyclooxygenase and 5-lipoxygenase in hamster and human oral cancer and chemopreventive effects of celecoxib and zileuton, manuscript in preparation. 
Received 4/28/04; revised 6/15/04; accepted 6/18/04.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  F. Cianchi, C. Cortesini, L. Magnelli, E. Fanti, L. Papucci, N. Schiavone, L. Messerini, A. Vannacci, S. Capaccioli, F. Perna, et al. Inhibition of 5-lipoxygenase by MK886 augments the antitumor activity of celecoxib in human colon cancer cells. Mol. Cancer Ther., November 1, 2006; 5(11): 2716 - 2726. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Sun, S. Sood, N. Li, D. Ramji, P. Yang, R. A. Newman, C. S. Yang, and X. Chen Involvement of the 5-lipoxygenase/leukotriene A4 hydrolase pathway in 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamster cheek pouch, and inhibition of carcinogenesis by its inhibitors Carcinogenesis, September 1, 2006; 27(9): 1902 - 1908. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Mayburd, A. Martlinez, D. Sackett, H. Liu, J. Shih, J. Tauler, I. Avis, and J. L. Mulshine Ingenuity Network-Assisted Transcription Profiling: Identification of a New Pharmacologic Mechanism for MK886. Clin. Cancer Res., March 15, 2006; 12(6): 1820 - 1827. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hoque, S. M. Lippman, T.-T. Wu, Y. Xu, Z. D. Liang, S. Swisher, H. Zhang, L. Cao, J. A. Ajani, and X.-c. Xu Increased 5-lipoxygenase expression and induction of apoptosis by its inhibitors in esophageal cancer: a potential target for prevention Carcinogenesis, April 1, 2005; 26(4): 785 - 791. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Li, S. Sood, S. Wang, M. Fang, P. Wang, Z. Sun, C. S. Yang, and X. Chen Overexpression of 5-Lipoxygenase and Cyclooxygenase 2 in Hamster and Human Oral Cancer and Chemopreventive Effects of Zileuton and Celecoxib Clin. Cancer Res., March 1, 2005; 11(5): 2089 - 2096. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Cell Growth & Differentiation |
