# Gastrointestinall Tumors: Phytochemical and Drug Combinations Targeting the Hallmarks of Cancer
## 4 Drugs and Phytochemicalasis against Gastrointestinal Tumors in Clinical Practice  
Several combinations of anticancer drugs and phytochemicals have reached Phase I, II or III of clinical trials concerning gastrointestinal tumors. Interestingly, the phytochemical curcumin has been used in combination with gemcitabine and celecoxib in a phase III clinical trial against colon neoplasm, in combination with irinotecan in a phase I clinical trial against metastatic colorectal cancer and also with capecitabine against rectal cancer in a phase II clinical trial [33]. Importantly, several case-control studies and cohort studies analyzed the relationship between vitamin D intake and the risk of colorectal cancer [146; 147]. These studies indicated that the relationship between the serum 25(OH)D3 level and colorectal cancer risk generally shows an inverse association [148; 149; 150; 151; 152]. Interestingly, it was demonstrated that daily administration of resveratrol (0.5-1 g/day, for 8 days) before surgery in patients with colorectal cancer could reduce the rate of tumor cell proliferation [153]. Importantly, it was shown that the phytochemicals extracted from green tea, in combination with sulindac, celecoxib, leptomycin B, DOX or cisplatin, in colon and esophageal cancer clinical trials reduced SOD and COX2 activity and showed antiproliferative effects [154]. Interestingly, a combination of misletoe extract and commonly used chemotherapeutic drugs (including DOX), can remarkably induce the apoptotic process in tumor cells in several clinical trials [81]. Furthermore, the combination therapy based on the misletoe extract and doxofluuridine significantly increased the health status and eosinophil and leukocyte counts in gastric cancer patients when compared to untreated patients [81]. Importantly, the therapy based on SRT501 (a resveratrol oral formulation) at the dose of 5 g daily for two weeks induced the cleavage of caspase 3 and the induction of the apoptotic process in malignant hepatic tissues of colon cancer patients with liver metastases [155]. Interestingly, it was shown that curcumin, in combination with several anticancer drugs and phytochemicals, in clinical trials of pancreatic and colon cancer, increased the levels of tumor suppressors Bax, Bak, p53 upregulated modulator of apoptosis (PUMA) and decreased the levels of oncoproteins Bcl-2, Bcl-xL, Nuclear factor erythroid 2-related factor 2 (Nrf2), VEGF, mechanistic target of rapamycin (mTOR), NF-kB, COX-2, pSTAT3, Matrix metallopeptidase 2 (MMP2) and MMP9 [156; 157; 158]. Regarding the use of the anticancer drug gemcitabine in combination with phytochemicals, in a phase I/II clinical trial in Japan, 21 patients affected by pancreatic cancer received a therapy based on the combination of gemcitabine and curcumin (8 g/day), noteworthy, no patient had a partial response and five had a stable disease [159]. Importantly, in this phase II clinical study, the curcumin plasma levels of the treated patients ranged from 29 to 412 ng/mL [159]. Interestingly, a therapy based on the combination of gemcitabine, curcumin and Celebrex was used in a phase III clinical trial against pancreatic and colon tumors [24]. Importantly, the combined effect of gemcitabine and curcumin against pancreatic cancer was evaluated in a phase II clinical trial [160]. Pancreatic cancer patients (\(n=17\)) were supplemented 8 g of curcumin daily for 4 weeks, in combination with gemcitabine; unluckily, this therapy was not able to significantly improve the clinical conditions of the patients [160]. Interestingly,genistein has been utilized also in combination with gemcitabine and erlotinib against metastatic pancreatic cancer in a recent Phase II clinical trial and the authors evidenced that the antitumor effect was exerted by the modulation of p-Akt and NF-kB levels, mediated by the combination of the phytochemical and the anticancer drugs [33].