Cancer Chemoprevention: A Strategic Approach Using Phytochemicals

Cancer chemoprevention approaches are aimed at preventing, delaying, or suppressing tumor incidence using synthetic or natural bioactive agents. Mechanistically, chemopreventive agents also aid in mitigating cancer development, either by impeding DNA damage or by blocking the division of premalignant cells with DNA damage. Several pre-clinical studies have substantiated the benefits of using various dietary components as chemopreventives in cancer therapy. The incessant rise in the number of cancer cases globally is an issue of major concern. The excessive toxicity and chemoresistance associated with conventional chemotherapies decrease the success rates of the existent chemotherapeutic regimen, which warrants the need for an efficient and safer alternative therapeutic approach. In this scenario, chemopreventive agents have been proven to be successful in protecting the high-risk populations from cancer, which further validates chemoprevention strategy as rational and promising. Clinical studies have shown the effectiveness of this approach in managing cancers of different origins. Phytochemicals, which constitute an appreciable proportion of currently used chemotherapeutic drugs, have been tested for their chemopreventive efficacy. This review primarily aims to highlight the efficacy of phytochemicals, currently being investigated globally as chemopreventives. The clinical relevance of chemoprevention, with special emphasis on the phytochemicals, curcumin, resveratrol, tryptanthrin, kaempferol, gingerol, emodin, quercetin genistein and epigallocatechingallate, which are potential candidates due to their ability to regulate multiple survival pathways without inducing toxicity, forms the crux of this review. The majority of these phytochemicals are polyphenols and flavanoids. We have analyzed how the key molecular targets of these chemopreventives potentially counteract the key drivers of chemoresistance, causing minimum toxicity to the body. An overview of the underlying mechanism of action of these phytochemicals in regulating the key players of cancer progression and tumor suppression is discussed in this review. A summary of the clinical trials on the important phytochemicals that emerge as chemopreventives is also incorporated. We elaborate on the pre-clinical and clinical observations, pharmacokinetics, mechanism of action, and molecular targets of some of these natural products. To summarize, the scope of this review comprises of the current status, limitations, and future directions of cancer chemoprevention, emphasizing the potency of phytochemicals as effective chemopreventives.

Rituximab With High-Dose Methotrexate In Newly Diagnosed Primary Central Nervous System Lymphoma: a Single-Center Experience From China

Induction chemotherapy based on high-dose methotrexate is considered as the standard approach for newly diagnosed primary central nervous system lymphomas (PCNSLs). However, the best combination chemotherapeutic regimen remains unclear. This study aimed to determine the efficacy and toxicities of rituximab with methotrexate (R-M regimen). Consecutive 37 Chinese patients receiving R-M regimen as induction chemotherapy were retrospectively identified from January 2015 to June 2020 from our center in eastern China. Fourteen patients receiving rituximab plus methotrexate with cytarabine (R-MA regimen) at the same period were identified as the positive control group. The response rates, survival, toxicities, length of hospital stay (LOS), and cost were compared. Compared with the R-MA regimen, the R-M regimen showed comparable response rate and survival outcomes, but had fewer grade 3-4 hematological toxicities, shorter LOS, lower mean total hospitalization cost and lower mean total antibiotic cost. Overall response after two cycles of chemotherapy, complete remission at the end of induction chemotherapy and ECOG>3 were independent prognostic factors for overall survival. In conclusion, R-M regimen is an effective and well-tolerated combination treatment for PCNSLs, which warrants further evaluation in randomized trials.

Abstract 17234: Cisplatin Induced Coronary Artery Atherosclerosis Leading To St-elevation Myocardial Infarction: A Case Report

Introduction: Cisplatin-based chemotherapeutic regimen (CBCR) is known for increasing risk of venous thromboembolic (TE) disease. We report a unique case of STEMI associated with CBCR which we believe was caused by coronary artery thrombosis. Case description: A 31-yo man with a past history of germ cell tumor presented with chest pain radiating to back and left arm. It started this morning and intensity did not worsen with exertion. He denied any dyspnea, diaphoresis or palpitations. He was non-smoker and non-obese. He denied any family history of premature coronary artery disease. He had undergone unilateral orchiectomy a year ago, and was currently receiving chemotherapy with bleomycin, etoposide and cisplatin; the last dose of his 3 rd cycle was given the day before. EKG showed ST elevation in leads I, aVL, V4 and V5. Troponin I was high to 6.9 ng/ml (ULN 0.045 ng/ml). He received intravenous infusion of thrombolytic. An angiogram done the next day showed moderate mid-LAD disease with residual clot. A CT scan and an echocardiogram later showed left ventricular thrombus (LVT). He was kept on therapeutic enoxaparin along with aspirin. Follow up echocardiogram showed resolution of the thrombus. His chemotherapy was stopped, and he has been kept on active surveillance since then. Discussion: Most cases of CBCR-associated myocardial infarction that have been reported have been seen in the older population with other risk factors for coronary artery disease. Cases where angiographic data was available, coronary artery vasospasm appeared to be the culprit rather than a true plaque rupture. While the presence of LVT raises possibility of thromboembolism to coronaries causing MI, the angiographic findings support accelerated plaque formation to be the cause of infarction. In earlier reports, elevated pre-treatment level of von Willebrand factor has been postulated to have some role in the disease pathogenesis. Other possible mechanisms for pathogenesis include endothelial cell damage, platelet activation, and imbalance between thromboxane-prostacyclin levels. This case emphasizes the need to keep cardiac etiologies of chest pain in the differential when evaluating patients on CBCR as timely intervention is life saving and prevent morbidity.

Efficacy of integrating short-course chemotherapy with Chinese herbs to treat multi-drug resistant pulmonary tuberculosis in China: a study protocol

Background Tuberculosis (TB) caused Mycobacterium tuberculosis (M.tb) is one of infectious disease that lead a large number of morbidity and mortality all over the world. Although no reliable evidence has been found, it is considered that combining chemotherapeutic drugs with Chinese herbs can significantly improves the cure rate and the clinical therapeutic effect. Methods Multi-drug resistant pulmonary tuberculosis (MDR-PTB, n = 258) patients with Qi-yin deficiency syndrome will be randomly assigned into a treatment group (n = 172) or control/placebo group (n = 86). The treatment group will receive the chemotherapeutic drugs combined with Chinese herbs granules (1 + 3 granules), while the control group will receive the chemotherapeutic drugs combined with Chinese herbs placebo (1 + 3 placebo granules). In addition, MDR-PTB (n = 312) patients with Yin deficiency lung heat syndrome will be randomly assigned to a treatment (n = 208) or control/placebo (n = 104) group. The treatment group will receive the chemotherapeutic regimen combined with Chinese herbs granules (2 + 4 granules), while the control group will receive the chemotherapeutic drugs and Chinese herbs placebo (2 + 4 placebo granules). The primary outcome is cure rate, the secondary outcomes included time to sputum culture conversion, lesion absorption rate and cavity closure rate. BACTEC™ MGIT™ automated mycobacterial detection system will be used to evaluate the M.tb infection and drug resistance. Chi-square test and Cox regression will be conducted with SAS 9.4 Statistical software to analyze the data. Discussion The treatment cycle for MDR-PTB using standardized modern medicine could cause lengthy substantial side effects. Chinese herbs have been used for many years to treat MDR-PTB, but are without high-quality evidence. Hence, it is unknown whether Chinese herbs enhances the clinical therapeutic effect of synthetic drugs for treating MDR-PTB. Therefore, this study will be conducted to evaluate the clinical therapeutic effect of combining Chinese herbs and chemotherapeutic drugs to treat MDR-PTB cases. It will assist in screening new therapeutic drugs and establishing treatment plan that aims to improve the clinical therapeutic effect for MDR-PTB patients. Trial registration This trial was registered at ClinicalTrials.gov (ChiCTR1900027720) on 24 November 2019 (prospective registered). Graphical Abstract

Neoadjuvant Chemotherapy Switch in Borderline Resectable/Locally Advanced Pancreatic Cancer

Background Neoadjuvant chemotherapy (NAC) is an integral part of preoperative treatment for patients with borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC). The identification of a chemotherapeutic regimen that is both effective and tolerable is critical for NAC to be of oncologic benefit. After initial first-line (FL) NAC, some patients have lack of response or therapeutic toxicities precluding further treatment with the same regimen; optimal decision making regarding this patient population is unclear. Chemotherapy switch (CS) may allow for a larger proportion of patients to undergo curative-intent resection after NAC. Methods We reviewed our surgical database for patients undergoing combinatorial NAC for BR/LA PDAC. Variant histologic exocrine carcinomas, intraductal papillary mucinous neoplasm-associated PDAC, and patients without research consent were excluded. Results Overall, 468 patients with BR/LA PDAC receiving FL chemotherapy were reviewed, of whom 70% (329/468) continued with FL chemotherapy followed by surgical resection. The remaining 30% (139/468) underwent CS, with 72% (100/139) of CS patients going on to curative-intent surgical resection. Recurrence-free survival (RFS) and overall survival (OS) were not significantly different between the resected FL and CS cohorts (30.0 vs. 19.1 months, p = 0.13, and 41.4 vs. 36.4 months, p = 0.94, respectively) and OS was significantly worse in those undergoing CS without subsequent resection (19 months, p < 0.0001). On multivariable analysis, carbohydrate antigen (CA) 19-9 and pathologic treatment responses were predictors of RFS and OS. Conclusion CS in patients undergoing NAC for BR/LA pancreatic cancer does not incur oncologic detriment. The incorporation of CS into NAC treatment sequencing may allow a greater proportion of patients to proceed to curative-intent surgery.

Cleome Viscosa Exhibits Cytotoxicity in Vitro and improves Tumor Inhibitory Properties in Vivo in Liquid Tumor Model

Cancer is one of the major causes of death in the world today. Although chemotherapeutic regimen remains the prime treatment of cancer, it is important to explore for newer compounds due to their adverse reactions and the growing rate of resistance. Traditionally, some plants are used for the treatment of cancers in India. However, no scientific data backing the evidence exists for the same. Among such plants is Cleome viscosa Linn, which is used in the Indian system of medicine for cancer treatment. To test its anticancer activity and generate scientifically reliable data, the extraction of whole plant has been carried out using methanol and fractions were generated using petroleum ether, dichloromethane, ethyl acetate and n-butanol. The fractions were first tested in vitro for their antiproliferative activity and mechanistic studies. In this paper, we report the anticancer potential of the fractions by a preliminary cytotoxicity activity in vitro using cell lines followed by the liquid tumor (EAC) model in mice. Upon screening on a panel of cancer cell lines, the fractions of petroleum ether, dichloromethane and ethyl acetate were found to possess significant cytotoxic activity on Hela and U343 cell lines. With this evidence, we have then tested the in vivo activity on mice using the liquid tumor model in which the fractions of pet ether, dichloromethane and ethyl acetate exhibit a potential anticancer activity which is evident in characteristics like inhibition of tumor progression, increase in the mean survival time and percentage increased life span along with a decrease in tumor volume. The fractions also showed significant anti-oxidant properties.

Encouraging Early Outcomes of Treatment With Arsenic Trioxide Combined With Chemotherapy for Alveolar Rhabdomyosarcoma in Children: 4 Case Reports

BackgroundAlveolar rhabdomyosarcoma (ARMS) is a subtype of rhabdomyosarcoma characterized by its aggressive behavior and poor prognosis, highlighting the need for novel treatment options. Arsenic trioxide (ATO) has been shown to specifically inhibit tumor growth and the metastasis of ARMS in vitro by acting on the hedgehog pathway. Here we report on a pilot clinical study to evaluate the activity of an ATO-combined chemotherapy approach for the treatment of ARMS patients.MethodsWe designed a therapeutic schedule of an ATO-combined chemotherapy, incorporating comprehensive management according to the Intergroup Rhabdomyosarcoma Study Group protocol. ATO was administered at 0.16 mg/kg per day over 8 h via an IV for 10 days combined with a chemotherapeutic regimen of vincristine, actinomycin, and cyclophosphamide (VAC regimen) on the third day, which was repeated every 21 days. A total of eight cycles of ATO-combined chemotherapy were applied throughout the entire scheme.ResultsA total of three refractory/recurrent and one untreated ARMS patient, three male and one female, with a median age of 5.8 years (range, 5.1 to 12.5 years), were enrolled in the present study. All patients were sensitive to combined chemotherapy with ATO and achieved partial or complete remission during treatment. Except for reversible gastrointestinal reaction and myelosuppression, no other adverse events were observed during the process of treatment.ConclusionsThe combined chemotherapy of ATO and the VAC regimen exhibited beneficial activities against ARMS in pediatrics and was well tolerated, but prospective large-scale clinical trials are warranted to determine the long-term efficacy, optimal courses, and late toxicity in this population.

Pharmacoethnicity of FOLFIRINOX versus gemcitabine plus nab-paclitaxel in metastatic pancreatic cancer: a systematic review and meta-analysis

Treatment outcomes between FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) and GNP (gemcitabine with albumin-bound paclitaxel) as first-line chemotherapy regimens for metastatic pancreatic cancer (PC) were assessed according to ethnic groups categorized as Western or Asian subgroups. PubMed, EMBASE, and Cochrane library were searched. Thirteen studies were eligible in this meta-analysis. Overall survival was not significantly different between FOLFIRINOX and GNP (HR 1.00, 95% CI 0.83–1.20, P = 0.990). However, the Western subgroup showed a higher survival benefit for FOLFIRINOX over GNP (HR 0.84, 95% CI 0.74–0.95, P = 0.006) whereas the Asian subgroup showed the survival benefit for GNP over FOLFIRINOX (HR 1.29, 95% CI 1.03–1.60, P = 0.030). Progression free survival was not significantly different between the two regimens in the Western subgroup (HR 1.01, 95% CI 0.84–1.20, P = 0.950) and the Asian subgroup (HR 1.13, 95% CI 0.97–1.33, P = 0.110). Occurrence of febrile neutropenia was significantly higher in FOLFIRINOX at both ethnic subgroups; however, that of peripheral neuropathy was significantly higher only in GNP of the Asian subgroup. Therefore, pharmacoethnicity might be a factor worth considering when deciding on a frontline chemotherapeutic regimen although the overall survival was not significantly different between FOLFIRINOX and GNP for metastatic PCs.