Xin-Yun Li,Zhen-Fei Xiong

1Hangzhou Xiaoshan First People Hospital,Zhejiang,China.2Hangzhou Xiaoshan TCM Hospital,Zhejiang,China.

Introduction

Chemotherapy-induced diarrhea(CID)is one of the most common chemotherapy side effects in cancer patients, especially with the highest incidence of fluorouracil and irinotecan[1].CID can not only cause the decrease of body's blood volume,lead to water and electrolyte imbalance,induce acute renal insufficiency,increase the incidence of infection,affect the patient's physique and quality of life, and even be life-threatening; and increase hospitalization costs,aggravate patient psychology Burden, reduce the therapeutic effect of tumors[2].

The main mechanism of CID

The mechanism of clinically induced CID is not well defined,and is associated with a variety of factors,including anti-tumor drugs which damage to the intestinal epithelial tissue,inflammation,infection,and the use of antibiotics. At present, mainly the chemotherapeutic drugs cause the destruction of the intestinal mucosa,the disproportionate increase and atypical hyperplasia of goblet cells and crypt cells,destroying the reabsorption function of microvilli cells,leading to an increase of intestinal fluid,eventually leading to the imbalance of intestinal absorption and secretory function, the pathogenesis of the most common drugs,fluorouracil and CPT-11,is as follows[3,4]:

Mechanism of CID caused by fluorouracil

5-FU(Fluorouracil)is phosphorylated into 5-FdUMP(5-fluorouracil deoxynucleotide) or 5-FUMP(5-pseudo-uridine nucleotide),which is sensitive to proliferating small intestinal cells and can cause intestinal mucosa injury,and interfere with the division of intestinal cells, causing cell wall necrosis and extensive inflammation of the intestinal wall,resulting in a change in the balance between the number of absorbed and secreted cells,leading to diarrhea[5].

Mechanism of caused by CPT-11

CPT-11 is rapidly hydrolyzed in vivo by carboxylesterase(CE)to the active metabolite SN-38.SN-38 can cause necrosis and apoptosis of intestinal epithelial cells, leading to absorption of water,electrolyte disorders and excessive secretion of intestinal fluid in the small intestine.Its concentration in the intestine and its contact with the intestinal epithelium are the key to delayed diarrhea[6].SN-38 causes mitotic arrest and apoptosis initiation in small intestine crypt cells and is associated with changes in epidermis absorbs fluff fulling off and the balance between the number of cells that are absorbed and secreted.Then,the inflammatory cells of the intestinal wall increase in permeability,and a large amount of water and electrolytes are secreted,which leads to diarrhea.

On one hand,in the liver,SN-38 is catalyzed by uridine diphosphate glucuronyltransferase 1A1(UDP-GT1A1 or UGT1A1)in hepatocyte microsomes to produce an inactive metabolite SN-38 glucuronide(SN-38G).Studies have shown that the intestinal flora plays an important role in the development of delayed diarrhea caused by CPT-11.The intestinal bacteria β-glucuronidase can re-transform SN-38-G into SN-38[7].On the other hand,the concentration of CPT-11 in the bile after administration is high.CPT-11 is secreted into the duodenum through bile and then excreted through the intestine.The CE activity in the small intestine is very high.The CPT-11 prototype that is discharged into the intestine can be directly converted into SN-38,resulting in SN-38 accumulation.

Polymorphisms in specific genes cause differences in enzyme activity that affect drug distribution and metabolism.Studies have shown that there are a large number of polymorphic sites in the UGT1A1 gene,and some site changes will affect the activity of the enzyme,which in turn affects the metabolism of chemical carcinogens. Therefore, the polymorphism of the UGT1A1 gene leads to a more serious toxicity of CPT-11,which needs to attract more attention[8].

At present,modern medicine mainly focuses on symptomatic treatment,including the following points:(1)use antidiarrheal drugs to reduce gastrointestinal motility and improve the defense effect of mucosal barrier on attack factors.Disadvantages:it is prone to slow gastrointestinal motility,and even gastrointestinal paralysis may occur. (2) Anti-infective treatment,mainly E. coli infection. Disadvantages: easy to destroy the normal flora (3) eating high-protein,high-calorie low-residue food,to avoid a stimulating diet of the gastrointestinal tract.Disadvantages:The small range of ingredients and the increased processing steps.(4)to supplement enough nutrients,maintain water and electrolyte balance,especially to prevent hypokalemia.(5)Octreotide is effective in controlling chemotherapy-related severe diarrhea and carcinoid syndrome-related diarrhea[9].

Research prospects of Chinese medicine in relieving chemotherapy related diarrhea

From the perspective of TCM,chemotherapy-related diarrhea can be attributed to the category of“diarrhea”.The causes of diarrhea are feeling exogenous evils,eating injuries,emotional dissatisfaction,insufficient endowment,and long-term illness,long-term viscera,weakness, etc. The main pathogenesis is spleen dampness,spleen and stomach transport dysfunction,disorders of separation of the clear and the turbid,failure to conduct and transmit.The cause of the tumor is mainly due to the six excesses, or dietary irregularities,or the seven-affect internal damage,and the lack of energy,spleen dysfunction,poisonous evil in the gastrointestinal tract, condensed into accumulation. Right vacuity is mainly spleen and stomach deficiency, then long-term caused kidney deficiency,lacking of Qi and blood.Evil repletion is based on phlegm,dampness,stasis,poison,stagnation,cold, heat, fire [10]. Therefore, the syndrome of chemotherapy-related diarrhea is spleen deficiency and dampness.Traditional Chinese medicine(TCM)often uses warm yang and move spleen and remove dampness as the basic method, syndrome differentiation and treatment,flexible compatibility,acupuncture and medicine combination, and multidisciplinary comprehensive treatment.

Although TCM has advantages in the treatment of CID, large-sample, multi-center, large-scale evidence-based medical research is still rare,and the mechanism of drug use is still lacking.Now this paper combines the known diarrhea mechanism. The mechanism of Chinese medicine treatment of CID is a prospect and conjecture,as shown in Figure 1 and Figure 2.

Regulation of intestinal mucosal water and liquid metabolism

Modern medical research shows that Chinese medicine can regulate intestinal mucosal water and liquid metabolism,and it is very likely that Chinese medicine treat CID through this mechanism.Intestinal water and liquid metabolism is disordered when happens diarrhea,Claudin-1, AQP3, AQP8, Na+/K-ATPase are functional proteins expressed in colonic mucosal epithelial cells,which can regulate colonic mucosal barrier structure and function,and intestinal mucosal cell transmembrane channels, intracellular ion homeostasis is involved in intestinal water metabolism[11].Zhou Cili et al confirm the effect of moxibustion and its products on visceral pain and colonic water metabolism in rats with diarrhea-type irritable bowel syndrome [12].Abdominal retraction (AWR) score was used to evaluate visceral pain, and immunohistochemistry was used to detect colonic Claudin-1, AQP3, AQP8, Na+/K-ATPase protein expression and other methods to detect the effects of moxibustion and other things like warm,light,smoke etc.produced by moxibustion on IBS model rats,and found that moxibustion can improve the colonic water metabolism and visceral pain in rats with IBS-D,so as to relieve the symptoms of diarrhea and abdominal pain in IBS-D rats.

Regulate intestinal flora to protect intestinal mucosa

Figure 1 Mechanism of CID generation

Figure 2 Mechanism of TCM treatment of chemotherapy-related diarrhea

TCM can also regulate the intestinal flora,protect the intestinal mucosa,coordinate intestinal peristalsis,and regulate the body's immunity.In recent years,research reports,diarrhea after CPT-11 chemotherapy is related to intestinal flora disorder,especially related to the increase of bacteria producing β-glucuronidase[13].The main flora is Bifidobacterium,Escherichia coli,Staphylococcus and Clostridium.The intestinal flora plays an important role in the maturation and regulation of the host's innate immune and adaptive immune systems,especially mucosal immunity in the intestine. Studies have shown that, Yunpizhixie decoction has the effect of improving the intestinal micro-ecological environment in children with persistent diarrhea of spleen deficiency[14].There are also single herb,such as"Liu shen qu"which regulates the intestinal flora of patients with IBS and can increase the number of beneficial bacteria in the intestine.Animal experiments have also shown that Huangqin improves intestinal mucosal damage,increases intestinal no content and decreases PCNA expression,and then has a preventive effect on delayed diarrhea caused by CPT-11[15].

Regulation of inflammatory factors

The occurrence of CID is also affected by various inflammatory factors, so inflammatory factors may play a role in the treatment of CID.Zhang Lianfeng et al observed the effect of Xianglianwan on the nude mice model of chemotherapy-associated diarrhea[16].It was found that Xianglianwan can reduce the concentration of proinflammatory cytokines IFN-γ and TNF-α in serum through inhibiting the activation of NF-KB P65 pathway,and increase the secretion of the anti-inflammatory factor IL-4, thereby reducing intestinal inflammation and intestinal damage. Xu Haizhen et al. found that WenzhongJianpitang can increase the expression of IL-10 in the mucosa,enhance its anti-inflammatory activity, regulate the level of anti-inflammatory/proinflammatory factors,and play a role in the treatment of diarrhea[17].

Acting on gene targets to affect gene expression

Although there is no clear research to prove that Chinese medicine can regulate the corresponding target gene,it has been shown that the polymorphism of uridine diphosphate glucuronyltransferase 1A1(UGT1A1)gene may affect CPT-11,which is one of the causes of adverse reactions such as diarrhea after chemotherapy,UGT1A1 is the most widely studied gene locus[13].Therefore,whether or not Chinese medicine treatment of CID can regulate the polymorphism of UGT1A1 gene remains one of the possible therapeutic mechanisms.

Regulating gastrointestinal hormones

Modern medicine believes that the movement,sensory and secretory functions of the gastrointestinal tract are regulated by the neuro-endocrine-immune network,the brain-intestinal axis. The material basis is various gastrointestinal hormones and neurotransmitters.Studies have shown that Chinese medicine can reduce 5-hydroxytryptamine (5-HT), vasoactive intestinal peptide(VIP),calcitonin gene-related peptide(CGRP)in IBS-D patients.Serum levels of CGRP can reduce the release of substance P(SP)in the colon of visceral hypersensitivity rats, and reduce the incidence of diarrhea by regulating the expression of SP and SPM RNA in the colon[18].There are also related studies about Chinese medicine can also improve the colonic movement and visceral sensitivity of rats with diarrhea by down-regulating the expression of 5-HT,5-HTR3 and 5-HTR4 in the brain [19].The above results indicate that Chinese medicine may play a role in improving gastrointestinal motility and visceral sensitivity by regulating the central or peripheral different levels of expression of 5-HT and other related gastrointestinal hormones.Since TCM can regulate gastrointestinal hormones,it is highly probable that medicine will improve diarrhea through this mechanism during the treatment of CID.

Conclusion

In summary,the author believes that the mechanism of Chinese medicine treatment of CID may regulate intestinal mucosal aqueous fluid metabolism,intestinal flora,protect intestinal mucosa;regulate inflammatory factors;act on gene targets to affect gene expression;regulate gastrointestinal hormones and other factors.Looking at the relevant literature,the author is not difficult to find that the research on the mechanism of CID treatment of TCM is still lacking,so this article wants to introduce it to start a discussion,summarize the more likely treatment mechanism to provide the corresponding basis for the next scientific research direction,and give reasonable things to future TCM treatment.

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