Abstract
Objective
The purpose of this study was to investigate the efficacy and safety of spinal-Z, derived from Peganum harmala seeds and Dracocephalum Kotschyi Boiss leaves, in patients with esophageal and stomach adenocarcinoma, and squamous cell carcinoma of the esophagus.
Methods
Sixty-one patients with malignancies of the upper gastrointestinal tract were randomly assigned to one of two groups (treatment or control) in a double-blind fashion. Six capsules of Spinal-Z were prescribed to the patients with the regimen of 600 mg/m2/day, and placebo to the control group, for six months.
Results
There were no significant differences between the two groups with regard to age, sex, duration of cancer, type of cancer and family history of cancer. There were significant differences in abdominal pain, heartburn, constipation and vomiting between the two groups, following spinal-Z therapy. Evaluation of drug side effects showed no difference in cough or other respiratory symptoms, itching, headache or dizziness between the two groups, both before and after treatment.
Conclusion
This study indicates that Spinal-Z is safe and efficacious in the management of patients with upper gastrointestinal tract cancers.
Keywords: Gastroesophageal cancers, Adenocarcinoma, Squamous cell carcinoma, Peganum harmala, Dracocephalum kotschyii Boiss, Spinal-Z
1. Introduction
Gastric cancer (GC) is one of the most common malignancies worldwide, with especially high mortality rates in Asia, Europe and South America (1). Because the prognosis for GC is poor and it is often diagnosed at a locally advanced or metastatic stage, the treatment remains challenging. In advanced and metastatic stages, the disease does not respond well to conventional treatments. Chemotherapy, radiotherapy, and surgery, the most common treatments modalities, are either poorly effective (2), and/ or have significant and severe side effects (3). Therefore, there are efforts to discover new therapeutic agents with low toxicity and fewer side effects.
It has been shown that neoplasms in the digestive organ are mostly due to modifications in dietary habits and natural plants and herbal remedies have been reported to have anti-cancer properties (4–11). Therefore, the use of easily accessible and inexpensive natural products and herbal drugs may have important therapeutic potential. Herbal drugs include plants, herbal complexes, or even a combination of plants, which have been used for thousands of years prior to the invention of chemical agents.
Spinal-Z is a methanolic compound, from the dried seeds of Peganum (Peganum harmala) and Dracocephalum Kotschyi Boiss leaves (12). Spinal-Z has cytotoxic, anti-inflammatory, analgesic, anti-bacterial and anti-virus effects (12).
The purpose of this study was to investigate the efficacy and safety of spinal-Z in patients with gastroesophageal adenocarcinoma and squamous cell carcinoma of the esophagus.
2. Materials and Methods
Subjects
This study was designed as a randomized, double-blind placebo-controlled trial and conducted at the Oncology Clinic of the Baqiyatallah Hospital, Tehran, Iran. Included in the study were 61 male and female subjects aged 25 to 75 years with histologically documented gastroesophageal cancer. Exclusion criteria were a history of hypersensitivity to herbal preparations, intolerance to chemotherapy, uncontrolled disease symptoms and the occurrence of severe adverse events during treatment.
The enrolled subjects were randomized to receive either Spinal-Z (600 mg/m2/day) (group T; n = 37) or placebo (group C; n = 24) for a period of 6 months. Placebo capsules contained starch and were matched in color and size to Spinal-Z capsules. All patients were under treatment with standard chemotherapy regimens appropriate for their respective cancer, and the chemotherapy regimens were maintained throughout the trial. The following chemotherapeutic agents were employed: 5-fluorouracil, uracil, and cisplatin. Patients were visited every two weeks and asked about their compliance and the regularity of consumption of the study medication, as well as any adverse effects. A board-certified oncologist visited patients at baseline and at the conclusion of the treatment period. The study was approved by the Ethics Committee of the Baqiyatallah University of Medical Sciences, and all participants gave written informed consent.
Biochemical analyses
Fasting blood samples were collected at baseline and at the end of the trial. Collected samples were centrifuged for 10 min to obtain serum. Serum samples were kept at − 80 °C until analysis. Biochemical parameters assessed in each sample were absolute neutrophil count, blood uric acid, serum creatinine, blood urea nitrogen, hemoglobin, hematocrit, platelets, white blood cells count, creatine phosphokinase, alanine transaminase and aspartate transaminase. Measurements were conducted using commercial enzyme immunoassay kits.
Statistical analysis
Statistical analyses were performed using the SPSS software version 17 (SPSS Inc., Chicago, Illinois, USA). Data were expressed as mean ±SD or number (%). Within-group comparisons were performed using a paired samples t-test (in the case of normal distribution of data) or Wilcoxon signed-ranks test (in the case of non-normal distribution of data). Between-group comparisons were made using independent samples t-test (in the case of normal distribution of data) or Mann –Whitney U-test (in the case of non-normal distribution of data). Categorical variables were compared using the chi-square test. Correlations of the evaluated parameters during the study were assessed using Pearson’s (in the case of normal distribution of data) or Spearman’s rank (in the case of non-normal distribution of data) correlation coefficients.
3. Results
Demographic data
The total number of males and females was 37 (60.7%) (T: 23, C:14) and 24 (39.3%) (T:14, C:10), respectively. There was no significant difference between the two groups in terms of gender (P=0.79).
Forty-four patients (78.6%) had gastric adenocarcinoma, while 3 (5.4%) had esophageal adenocarcinoma and nine patients (16.1%) had esophageal squamous cell carcinoma. There was no significant difference (P=0.94) between treatment and control groups with regards to cancer type.
Approximately, 50 patients (82%) had a family history of cancer. One of them (1.6%) had a family history of esophageal cancer. Four patients (6.6%) had a family history of gastric cancer, and six patients (9.8%) had a history of other cancer types. There was no significant difference between the treatment and control groups in terms of family history of cancer (P=0.81) (Table 1).
Table 1.
Demographic data of each patient group
| Categorical Variables | Level | Drug (N=37) | Placebo (N=24) | Total (N=61) | P value | |||
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| N | % | N | % | N | % | |||
| Sex | Male | 23 | 62.2% | 14 | 58.3% | 37 | 60.7% | 0.794 |
| Female | 14 | 37.8% | 10 | 41.7% | 24 | 39.3% | ||
|
| ||||||||
| Cancer Family History | No | 30 | 81.1% | 20 | 83.3% | 50 | 82.0% | 0.816 |
| Esophagus | 1 | 2.7% | 0 | .0% | 1 | 1.6% | ||
| Stomach | 2 | 5.4% | 2 | 8.3% | 4 | 6.6% | ||
| Other part | 4 | 10.8% | 2 | 8.3% | 6 | 9.8% | ||
|
| ||||||||
| Underling Disease | No | 22 | 61.1% | 18 | 75.0% | 40 | 66.7% | 0.181 |
| Hypertension | 5 | 13.9% | 1 | 4.2% | 6 | 10.0% | ||
| Diabetes | 5 | 13.9% | 1 | 4.2% | 6 | 10.0% | ||
| Hypertension & diabetes | 2 | 5.6% | 0 | .0% | 2 | 3.3% | ||
| Other | 2 | 5.6% | 4 | 16.7% | 6 | 10.0% | ||
|
| ||||||||
| Cancer Type | Esophageal squamous cell carcinoma | 6 | 17.1% | 3 | 14.3% | 9 | 16.1% | 0.945 |
| Esophageal adenocarcinoma | 2 | 5.7% | 1 | 4.8% | 3 | 5.4% | ||
| stomach adenocarcinoma | 27 | 77.1% | 17 | 81.0% | 44 | 78.6% | ||
|
| ||||||||
| Radiotherapy History | Yes | 9 | 25.0% | 9 | 37.5% | 18 | 30.0% | 0.391 |
| No | 27 | 75.0% | 15 | 62.5% | 42 | 70.0% | ||
Only 18 patients (30%) had a history of radiotherapy, while 42 patients (70%) had no history of radiation therapy (Table 1). There was no difference between the treatment and control groups in terms of a history of radiotherapy (P=0.39). The average age in the female and male subjects was 59.79±10.06 and 63.39±10.41 years, respectively. There was no difference between the two genders regarding age (P=0.09).
Laboratory measurements before and after the trial
The average hemoglobin (Hb) level in the drug treatment group was significantly increased from 11.59±1.41 milligrams (mg)/ deciliter (dl) to 12.15±1.48 mg/dl after spinal-Z (P<0.01). Similarly, the mean of Hb in the placebo group was significantly (P=0.04) increased from 11.26±1.42 mg/dl to 11.71±1.08 mg/dl after treatment. The mean of Hb before and after treatment did not show a difference between the treatment and control groups (P=0.44). The mean (Hct) in the drug group before and after treatment was 36.48%±4.84% and 37.70%±4.83%, respectively (P=0.01). The mean Hct was also significantly increased (P=0.02) from 34.92%±3.57 % before treatment to 36.18%±2.47% after treatment in the placebo group. The average for Hct before and after treatment did not show a difference between the treatment and control groups (P=0.67) (Table 2).
Table 2.
Laboratory criteria before and after treatment in two groups
| Variables | Group | Before | After | diff | P value | P value | ||
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| Mean | SD | Mean | SD | |||||
| Hgb | Drug | 11.59 | 1.41 | 12.15 | 1.48 | .56 | .006 | 0.448 |
| Placebo | 11.26 | 1.42 | 11.71 | 1.08 | .45 | .042 | ||
|
| ||||||||
| Hct | Drug | 36.48 | 4.84 | 37.70 | 4.83 | 1.22 | .010 | 0.670 |
| Placebo | 34.92 | 3.57 | 36.18 | 2.47 | 1.25 | .027 | ||
|
| ||||||||
| WBC | Drug | 7.02 | 2.58 | 6.44 | 2.23 | −.58 | .074 | 0.611 |
| Placebo | 7.20 | 2.51 | 6.76 | 1.56 | −.43 | .422 | ||
|
| ||||||||
| Pit | Drug | 220.80 | 52.88 | 216.06 | 51.83 | −4.73 | .593 | 0.691 |
| Placebo | 264.27 | 129.04 | 247.00 | 88.65 | −17.27 | .301 | ||
|
| ||||||||
| MCV | Drug | 85.52 | 5.68 | 84.34 | 6.16 | −1.17 | .268 | 0.495 |
| Placebo | 81.54 | 8.62 | 80.60 | 7.45 | −.94 | .380 | ||
|
| ||||||||
| Neutrophil | Drug | 59.68 | 12.53 | 61.07 | 12.64 | 1.39 | .419 | 0.828 |
| Placebo | 60.44 | 10.55 | 62.26 | 13.04 | 1.82 | .468 | ||
|
| ||||||||
| Basophil | Drug | 1.42 | 1.96 | 2.09 | 1.81 | .66 | .151 | 0.541 |
| Placebo | 1.46 | 1.63 | 2.42 | 1.51 | .95 | .035 | ||
|
| ||||||||
| Lymphocyte | Drug | 32.62 | 14.30 | 31.09 | 13.04 | −1.53 | .485 | 0.235 |
| Placebo | 32.37 | 12.98 | 38.08 | 27.46 | 5.71 | .423 | ||
|
| ||||||||
| BUN | Drug | 21.7 | 10.11 | 20.90 | 10.07 | −.80 | .424 | 0.170 |
| Placebo | 18.58 | 7.55 | 20.37 | 6.85 | 1.78 | .104 | ||
|
| ||||||||
| Cr | Drug | 1.03 | .36 | 1.04 | .24 | .005 | .915 | 0.313 |
| Placebo | .90 | .29 | .91 | .30 | .008 | .903 | ||
|
| ||||||||
| Uric Acid | Drug | 4.66 | 1.05 | 4.66 | .74 | .003 | .986 | 0.678 |
| Placebo | 4.80 | .80 | 4.78 | .58 | −.017 | .920 | ||
|
| ||||||||
| ALT | Drug | 31.05 | 30.08 | 30.43 | 26.73 | −.61 | .778 | 0617 |
| Placebo | 17.91 | 7.21 | 20.88 | 8.72 | 2.97 | .112 | ||
|
| ||||||||
| AST | Drug | 27.86 | 24.41 | 26.4 | 19.73 | −1.46 | .327 | 0.715 |
| Placebo | 20.35 | 7.82 | 21.53 | 5.12 | 1.17 | .292 | ||
|
| ||||||||
| ALP | Drug | 319.36 | 377.60 | 277.86 | 220.19 | 19.50 | .336 | 0.462 |
| Placebo | 194.11 | 51.54 | 195.47 | 45.84 | 1.35 | .660 | ||
The average white blood cell (WBC) count in the drug group was unchanged before (7.02±2.58 mg/dl) and after treatment (6.44±2.33 mg/dl) (P=0.07). The mean WBC count was also unchanged before (7.20±2.51 mg/dl) and after treatment (6.76±1.56 mg/dl) (P=0.42), and there was no difference in mean WBC count between the treatment and control groups (P=0.61). No hepatic enzyme changes were seen (ALT, AST and ALP) between spinal-Z and placebo treatment (P>0.05). Laboratory data are presented in Table 2. There were no significant differences between the treatment and control groups before and after treatment for any other laboratory parameters.
Investigation of gastrointestinal complaints
In the treatment group, 13 patients (43.3%) complained of abdominal pain before treatment, and this significantly decreased to 4 patients (13.3%) after treatment (P=0.004). In the placebo group, 8 patients (50%) complained of abdominal pain before treatment, and this decreased to 4 patients (25%) after treatment, but this was not significant (P=0.21). However, there was no difference regarding abdominal pain between the treatment and control groups before and after treatment (P=0.08) (Table 3).
Table 3.
Gastrointestinal complaints in both groups before and after treatment
| Group | Variables | Before | after | diff | P value | P value | ||
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| N | % | N | % | |||||
| Abdominal Pain (Positive) | Drug | 13 | 43.3% | 4 | 13.3% | −30% | 0.004 | 0.084 |
| Placebo | 8 | 50.0% | 4 | 25.0% | −25% | 0.219 | ||
|
| ||||||||
| Anorexia (Positive) | Drug | 19 | 63.3% | 3 | 10% | −53.3% | <0.001 | 0.863 |
| Placebo | 8 | 50.0% | 2 | 12.5% | −37.5% | 0.109 | ||
|
| ||||||||
| Heart Bum (Positive) | Drug | 14 | 46.7% | 10 | 33.3% | −13.4% | 0.388 | 0.028 |
| Placebo | 8 | 50.0% | 7 | 43.8% | −6.2% | 0.999 | ||
|
| ||||||||
| Constipation (Positive) | Drug | 8 | 26.7% | 1 | 3.3% | −23.4% | 0.016 | <0.001 |
| Placebo | 4 | 25.0% | 4 | 25.0% | 0% | 0.999 | ||
|
| ||||||||
| Nausea (Positive) | Drug | 11 | 36.7% | 5 | 16.7% | −20% | 0.070 | 0.045 |
| Placebo | 4 | 25.0% | 1 | 6.3% | −18.7% | 0.375 | ||
|
| ||||||||
| Vomiting (Positive) | Drug | 7 | 23.3% | 3 | 10.0% | −13.3% | 0.289 | 0.261 |
| Placebo | 3 | 18.8% | 3 | 18.8% | 0% | 0.999 | ||
19 patients (63.3%) in group T had complained about anorexia prior to treatment. After the trial, the number of patients with this complaint decreased to three (10%) (P<0.001). In the placebo group, 8 patients (50%) complained about anorexia before treatment and whilst this fell to 2 patients (12.5%) after treatment, this difference was not significant (P=0.1). The between-group comparison of anorexia showed no difference (P=0.86) (Table 3).
In the patients receiving Spinal-Z, 14 patients (46.7%) reported heartburn and 8 patients (26.7%) reported constipation before treatment that decreased to 10 patients (33.3%) reporting heartburn and only one patient (3.3%) reporting constipation after treatment (P=0.38 and P=0.01, respectively). In the placebo group, 8 patients (50%) reported heartburn and 4 patients (25%) reported constipation before treatment that did not differ after 6 months (P=0.99, P=0.99, respectively). Overall, there was a significant difference in terms of heartburn and constipation between the treatment and control groups before and after treatment (P = 0.02 and P<0.001) (Table 3).
In the treatment group, 11 subjects (36.7%) and seven subjects (23.3%) had complained of nausea and vomiting, respectively, before the treatment, but this did not differ after treatment (five patients (16.7%) and three patients (10%), P=0.07, P=0.28, respectively) In the placebo group, 4 cases (25%) and 3 cases (18.8%) complained of nausea and vomiting, respectively, before the start of the trial, but this did not differ after treatment (one patient (6.3%) and three patients (10%), P=0.37, P=0.99, respectively). Overall, there was a significant difference in terms of nausea between the treatment and control groups before and after the treatment (P = 0.04) but not for vomiting (P = 0.26) (Table 3).
Evaluation of drug side effects
Spinal-Z side effects evaluation showed a significant difference only regarding muscle weakness between two groups. Other side effects, including cough and respiratory symptoms, itching, headache and dizziness did not show any significant difference before and after treatment between groups T and C (Table 4).
Table 4.
Evaluation of drug side effects in both groups before and after treatment
| Group | Variables | Before | After | difF | p value | p value | ||
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| N | % | N | % | |||||
| Cough (Positive) | Drug | 12 | 40% | 1 | 3.3% | −36.7% | 0.001 | 0.167 |
| Placebo | 2 | 12.5% | 2 | 12.5% | 0% | 0.999 | ||
|
| ||||||||
| Respiratory (Positive) | Drug | 8 | 27.6% | 1 | 3.4% | −24.2% | 0.016 | 0.998 |
| Placebo | 4 | 25.0% | 1 | 6.3% | −18.7% | 0.250 | ||
|
| ||||||||
| Muscle weakness (Positive) | Drug | 16 | 55.2% | 5 | 17.2% | −38% | 0.001 | 0.032 |
| Placebo | 7 | 43.8% | 4 | 25.0% | −18.8% | 0.275 | ||
|
| ||||||||
| Itching (Positive) | Drug | 4 | 13.8% | 1 | 3.4% | −10.4% | 0.375 | 0.999 |
| Placebo | 1 | 6.3% | 0 | 0% | −6.3% | 0.999 | ||
|
| ||||||||
| Headache (Positive) | Drug | 8 | 27.6% | 1 | 3.4% | −24.2% | 0.016 | 0.999 |
| Placebo | 3 | 18.8% | 0 | 0% | −18.8% | 0.999 | ||
|
| ||||||||
| Dizziness (Positive) | Drug | 8 | 27.6% | 0 | 0% | −27.6% | <0.001 | 0.999 |
| Placebo | 6 | 37.5% | 0 | 0% | −37.5% | <0.001 | ||
4. Discussion
Stomach and esophageal cancers are two cancers of the gastrointestinal tract with a very poor prognosis (13). Gastric cancer is one of the leading causes of death with only a 5–20% survival rate (14). The 6-year and 10-year survival rate among patients with squamous cell carcinoma of the esophagus reported to be 39.5 % and 12%, respectively (15). Recent findings have shown that of 1,000 Iranian people, 21 patients with cancer of the upper digestive tract die each year (16). These observations indicate the need for improved risk identification and earlier tumour detection facilitating early treatment strategies (15, 17). Different treatment regimens for esophagus and gastric cancer are well documented (18–27) and include: Docetaxel, cisplatin, and fluorouracil (20–22); epirubicin, cisplatin, and fluorouracil (18); fluorouracil, leucovorin, and irinotecan(24); fluorouracil, leucovorin, and oxaliplatin (23); capecitabine and irinotecan (25); capecitabine and oxaliplatin (26). No single standard treatment regimen has been found to be superior for gastro-esophageal cancer (28).
In cases of gastric adenocarcinoma, surgical removal of all or part of the stomach is the only treatment that can cure the disease (29). In the advanced stages, symptom relief is the more critical issue. Radiotherapy or chemotherapy alone after surgery has no effect on survival rate, but simultaneous use of them is effective. The two main drugs in cancer chemotherapy are cisplatin and 5-FU that have a long track record of use (29, 30).
In our randomized double-blind study of Spinal Z versus placebo there was no difference in the patient demographics. The mean age of cancer in the female patients was lower than in the male patients, and could indicate an early diagnosis of cancer in females compared to males. The main symptomatic complaints of the study patients were dysphagia, abdominal pain, constipation, anorexia, and dyspepsia. For abdominal pain, anorexia, and constipation symptoms, there was a significant reduction in the Spinal Z group, whereas in patients who received placebo showed no symptomatic changes, suggesting the effectiveness of Spinal-Z in this patient cohort.
An improved therapeutic effect was shown in a clinical trial by Rezvani and colleagues by utilizing oxaliplatin instead of cisplatin and capecitabine instead of 5-FU in patients with advanced gastric cancer (31). Mean progression-free survival (PFS) was seven months and mean overall survival (OS) of patients was 10.6 months. The results of this study, in patients with inoperable and metastatic gastric cancer, demonstrated that a regimen consisting of EXE (Epirubicin, Xeloda, Eloxatin) once every three weeks is effective and tolerable, and can be given on an outpatient basis (31).
Seilanian Toosi and colleagues evaluated chemotherapy and radiotherapy before surgery and after surgery in patients with esophageal squamous cell carcinoma (32). This retrospective cohort study, from 2000 to 2005 was performed on 75 patients with esophageal cancer. 42 patients received at least treatments of adjuvant chemotherapy containing Cisplatin and 5-fluorouracil. According to the results of this study, there was a complete response to therapy before surgery in 5 patients (7/6%) with a median follow-up of 13 months. Recurrence occurred in 21 patients (28%), including nine with local regional recurrence, nine with distant metastases, and three with local and distant recurrence occurring simultaneously. For all patients, three-year survival was 62.2%. The survival rate in patients who had received at least three cycles of chemotherapy compared to patients who received less than three cycles or received no chemotherapy did not differ (P=0.09). Patients with class I and II tumors had a significantly improved survival compared with the III class (P=0.05) (32).
In another study, Yazdanbod and colleagues evaluated Spinal-Z for the treatment of cancer of the upper gastrointestinal tract (33). This study was performed over nine months in seven patients. These patients were enrolled voluntarily at different intervals. After the start of treatment, during the first visit and at follow up checks, one patient showed raised liver enzymes (AST, ALT, and bilirubin). This patient died with a diagnosis of drug-induced hepatitis (hepatitis fulminant) though causality to spinal-Z was not shown; however, assessment of Spinal-Z side effects on the liver is therefore important and further research is necessary. One patient died at an early stage with a diagnosis of myocardial infarction (MI). In another patient, serial sonography showed a decrease in growth of metastatic tumors. In other patients, common side effects such as dizziness and nausea were reported (33).
In the study presented here, two plants, including P. harmala and D. Kotschyi, were employed in the Spinal-Z preparation as palliative therapy in patients with esophageal squamous cell carcinoma and stomach adenocarcinoma, and to improve quality of life in these patients. No alteration in the blood cell count, liver, renal function tests and inflammatory profile was detected.
Alkaloids of harmala plants have multiple effects, including analgesic (34), anti-inflammatory (35) and cytotoxic (36), and inhibitory effects on the enzyme topoisomerase that induces programmed cell death and accelerates cancer cell death (37). These compounds also have antioxidant and anti-mutagenic effects (38, 39). The Spinal-Z capsule is a dried extarct of harmala beans that has three alkaloids (harman, harmine, harmaline) plus leaves of D. Kotschyi that contain the flavonoid xanthomicrol, which has anti-tumor properties and exerts its anti-tumor effect through inhibition of DNA isomerase (17). This flavonoid has also analgesic and sedative effects in cancer patients, exerted via blocking of the H2 receptor and inhibition of monoamine oxidase (MAO) (34, 40).
5. Conclusion
Results of this study indicated that spinal-Z was safe for use in the management of symptoms in patients with non-metastatic gastro-esophageal cancer. Further trials are warranted to investigate the impact and efficacy of this herbal preparation as an adjuvant therapy in patients with cancer.
Footnotes
This paper meets the requirements of KS X ISO 9706, ISO 9706-1994 and ANSI/NISO Z39.48-1992 (Permanence of Paper).
References
- 1.Tepes B. Can gastric cancer be prevented? J Physiol Pharmacol. 2009;60(Suppl 7):71–7. [PubMed] [Google Scholar]
- 2.Yang G, Li X, Li X, Wang L, Li J, Song X, et al. Traditional chinese medicine in cancer care: a review of case series published in the chinese literature. Evid Based Complement Alternat Med. 2012;2012:751046. doi: 10.1155/2012/751046. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Qi F, Li A, Inagaki Y, Gao J, Li J, Kokudo N, et al. Chinese herbal medicines as adjuvant treatment during chemo- or radio-therapy for cancer. Biosci Trends. 2010;4(6):297–307. [PubMed] [Google Scholar]
- 4.Toledo AL, Koifman RJ, Koifman S, Marchioni DM. Dietary patterns and risk of oral and pharyngeal cancer: a case-control study in Rio de Janeiro, Brazil. Cad Saude Publica. 2010;26(1):135–42. doi: 10.1590/S0102-311X2010000100014. [DOI] [PubMed] [Google Scholar]
- 5.Iranshahi M, Sahebkar A, Hosseini ST, Takasaki M, Konoshima T, Tokuda H. Cancer chemopreventive activity of diversin from Ferula diversivittata in vitro and in vivo. Phytomedicine. 2010;17(3–4):269–73. doi: 10.1016/j.phymed.2009.05.020. [DOI] [PubMed] [Google Scholar]
- 6.Iranshahi M, Sahebkar A, Takasaki M, Konoshima T, Tokuda H. Cancer chemopreventive activity of the prenylated coumarin, umbelliprenin, in vivo. Eur J Cancer Prev. 2009;18(5):412–5. doi: 10.1097/CEJ.0b013e32832c389e. [DOI] [PubMed] [Google Scholar]
- 7.Mirzaei H, Naseri G, Rezaee R, Mohammadi M, Banikazemi Z, Mirzaei HR, et al. Curcumin: A new candidate for melanoma therapy? Int J Cancer. 2016;139(8):1683–95. doi: 10.1002/ijc.30224. [DOI] [PubMed] [Google Scholar]
- 8.Momtazi AA, Shahabipour F, Khatibi S, Johnston TP, Pirro M, Sahebkar A. Curcumin as a MicroRNA regulator in cancer: A review. Rev Physiol Biochem Pharmacol. 2016;171:1–38. doi: 10.1007/112_2016_3. [DOI] [PubMed] [Google Scholar]
- 9.Shahabipour F, Caraglia M, Majeed M, Derosa G, Maffioli P, Sahebkar A. Naturally occurring anti-cancer agents targeting EZH2. Cancer Lett. 2017;400:325–35. doi: 10.1016/j.canlet.2017.03.020. [DOI] [PubMed] [Google Scholar]
- 10.Shakeri A, Sahebkar A. Anti-cancer products from marine sponges: Progress and promise. Recent Patents on Drug Delivery and Formulation. 2015;9(3):187–8. doi: 10.2174/1872211309666150529131549. [DOI] [PubMed] [Google Scholar]
- 11.Teymouri M, Pirro M, Johnston TP, Sahebkar A. Curcumin as a multifaceted compound against human papilloma virus infection and cervical cancers: A review of chemistry, cellular, molecular, and preclinical features. BioFactors. 2017;43(3):331–346. doi: 10.1002/biof.1344. [DOI] [PubMed] [Google Scholar]
- 12.Jahaniani F, Ebrahimi SA, Rahbar-Roshandel N, Mahmoudian M. Xanthomicrol is the main cytotoxic component of Dracocephalum kotschyii and a potential anti-cancer agent. Phytochemistry. 2005;66(13):1581–92. doi: 10.1016/j.phytochem.2005.04.035. [DOI] [PubMed] [Google Scholar]
- 13.Murphy AG, Lynch D, Kelly RJ. State of the art management of metastatic gastroesophageal cancer. Ann Transl Med. 2015;3(16):236. doi: 10.3978/j.issn.2305-5839.2015.09.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86. doi: 10.1002/ijc.29210. [DOI] [PubMed] [Google Scholar]
- 15.Simsa J, Leffler J, Hoch J, Linke Z, Padr R. Gastric cancer in young patients — is there any hope for them? Acta Chir Belg. 2004;104(6):673–6. doi: 10.1080/00015458.2004.11679641. [DOI] [PubMed] [Google Scholar]
- 16.Ahmadlou N, Omidvari SH, Mosalaei A. Results of Post-operative Radiotherapy in Patients withHigh Risk Gastric Cancer. J Med Res. 2003;1(3):43–9. [Google Scholar]
- 17.Cordell GA, Beecher CW, Pezzuto JM. Can ethnopharmacology contribute to the development of new anticancer drugs? J Ethnopharmacol. 1991;32(1–3):117–33. doi: 10.1016/0378-8741(91)90110-Y. [DOI] [PubMed] [Google Scholar]
- 18.Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, et al. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol. 1997;15(1):261–7. doi: 10.1200/JCO.1997.15.1.261. [DOI] [PubMed] [Google Scholar]
- 19.Wang J, Xu R, Li J, Bai Y, Liu T, Jiao S, et al. Randomized multicenter phase III study of a modified docetaxel and cisplatin plus fluorouracil regimen compared with cisplatin and fluorouracil as first-line therapy for advanced or locally recurrent gastric cancer. Gastric Cancer. 2016;19(1):234–44. doi: 10.1007/s10120-015-0457-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006;24(31):4991–7. doi: 10.1200/JCO.2006.06.8429. [DOI] [PubMed] [Google Scholar]
- 21.Ajani JA, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, et al. Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma: the V-325 Study Group. J Clin Oncol. 2007;25(22):3205–9. doi: 10.1200/JCO.2006.10.4968. [DOI] [PubMed] [Google Scholar]
- 22.Ajani JA, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, et al. Quality of life with docetaxel plus cisplatin and fluorouracil compared with cisplatin and fluorouracil from a phase III trial for advanced gastric or gastroesophageal adenocarcinoma: the V-325 Study Group. J Clin Oncol. 2007;25(22):3210–6. doi: 10.1200/JCO.2006.08.3956. [DOI] [PubMed] [Google Scholar]
- 23.Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008;26(9):1435–42. doi: 10.1200/JCO.2007.13.9378. [DOI] [PubMed] [Google Scholar]
- 24.Bouche O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, et al. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004;22(21):4319–28. doi: 10.1200/JCO.2004.01.140. [DOI] [PubMed] [Google Scholar]
- 25.van Meerten E, Eskens FA, van Gameren EC, Doorn L, van der Gaast A. First-line treatment with oxaliplatin and capecitabine in patients with advanced or metastatic oesophageal cancer: a phase II study. Br J Cancer. 2007;96(9):1348–52. doi: 10.1038/sj.bjc.6603750. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Moehler M, Kanzler S, Geissler M, Raedle J, Ebert MP, Daum S, et al. A randomized multicenter phase II study comparing capecitabine with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2010;21(1):71–7. doi: 10.1093/annonc/mdp269. [DOI] [PubMed] [Google Scholar]
- 27.Hong YS, Song SY, Lee SI, Chung HC, Choi SH, Noh SH, et al. A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Ann Oncol. 2004;15(9):1344–7. doi: 10.1093/annonc/mdh343. [DOI] [PubMed] [Google Scholar]
- 28.Prithviraj GK, Baksh K, Fulp W, Meredith K, Hoffe S, Shridhar R, et al. Carboplatin and paclitaxel as first-line treatment of unresectable or metastatic esophageal or gastric cancer. Dis Esophagus. 2015;28(8):782–7. doi: 10.1111/dote.12279. [DOI] [PubMed] [Google Scholar]
- 29.Petrelli F, Zaniboni A, Coinu A, Cabiddu M, Ghilardi M, Sqroi G, et al. Cisplatin or Not in Advanced Gastric Cancer: A Systematic Review and Meta-Analysis. PLoS ONE. 2013;8(12):e83022. doi: 10.1371/journal.pone.0083022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Wohrer SS, Raderer M, Hejna M. Palliative chemotherapy for advanced gastric cancer. Ann Oncol. 2004;15(11):1585–95. doi: 10.1093/annonc/mdh422. [DOI] [PubMed] [Google Scholar]
- 31.Rezvani H, Attarian H, Ghadyani M, Abasahl A. Eloxatin (Oxaliplatin), Xeloda (Capecitabine) and Epirubicin (EXE) as First Line Treatment in Metastatic Gastric Carcinoma. Iranian Journal of Surgery. 2008;16(3):26–33. [Google Scholar]
- 32.Seilanian Toosi M, Aledavood SA, Anvari K, Nowferesti G, Mohtashami S. The treatment outcome of definitive chemoradiotherapy in patients with esophageal squamous cell carcinoma. Journal of Gorgan University of Medical Sciences. 2007;9(3):22–9. [Google Scholar]
- 33.Yazdanbod A, Sadeghifard N, Niknam M. Therapeutic effects, adverse events and Spinal-z pharmaceutical indicators in the treatment of cancer of the upper gastrointestinal tract Ardebil. Iran: Ardebil University of Medical Sciences; 2001. [Google Scholar]
- 34.Shoaib M, Shah SW, Ali N, Shah I, Ullah S, Ghias M, et al. Scientific investigation of crude alkaloids from medicinal plants for the management of pain. BMC Complement Altern Med. 2016;16(1):178. doi: 10.1186/s12906-016-1157-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Hamsa TP, Kuttan G. Harmine inhibits tumour specific neo-vessel formation by regulating VEGF, MMP, TIMP and pro-inflammatory mediators both in vivo and in vitro. Eur J Pharmacol. 2010;649(1–3):64–73. doi: 10.1016/j.ejphar.2010.09.010. [DOI] [PubMed] [Google Scholar]
- 36.Lamchouri F, Zemzami M, Jossang A, Abdellatif A, Israili ZH, Lyoussi B. Cytotoxicity of alkaloids isolated from Peganum harmala seeds. Pak J Pharm Sci. 2013;26(4):699–706. [PubMed] [Google Scholar]
- 37.Sobhani AM, Ebrahimi SA, Mahmoudian M. An in vitro evaluation of human DNA topoisomerase I inhibition by Peganum harmala L. seeds extract and its beta-carboline alkaloids. J Pharm Pharm Sci. 2002;5(1):19–23. [PubMed] [Google Scholar]
- 38.Soliman AM, Abu-El-Zahab HS, Alswiai GA. Efficacy evaluation of the protein isolated from Peganum harmala seeds as an antioxidant in liver of rats. Asian Pac J Med. 2013;6(4):285–95. doi: 10.1016/S1995-7645(13)60058-9. [DOI] [PubMed] [Google Scholar]
- 39.Pisoschi AM, Pop A, Cimpeanu C, Predoi G. Antioxidant Capacity Determination in Plants and Plant-Derived Products: A Review. Oxid Med Cell Longev. 2016;2016:9130976. doi: 10.1155/2016/9130976. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Herraiz T, Gonzalez D, Ancin-Azpilicueta C, Aran VJ, Guillen H. beta-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO) Food Chem Toxicol. 2010;48(3):839–45. doi: 10.1016/j.fct.2009.12.019. [DOI] [PubMed] [Google Scholar]