The Effectiveness And Mechanism Of Tonifying Kidney And Spleen Method On Preventing And Treatment Of Myelosuppression Induced By Adjuvant Chemotherapy Of Colorectal Cancer Ⅲ

2. Western medicine treatment of bone marrow suppression

2.1 Prevention and treatment of leukopenia/neutropenia

Leukocytes and neutrophils are the basis of the body's defense function. Therefore, leukopenia can easily induce various infections. In more serious cases, such as febrile neutropenia (FN), antibiotics must be used, which often leads to prolonged hospitalization and even endangers the patient's life. Neutrophils stay in the blood vessels for less than 10 hours[54] and are often the first to be affected after chemotherapy. Therefore, prevention and treatment of leukopenia is crucial in chemotherapy for tumors.

The National Comprehensive Cancer Network (NCCN) clinical guidelines[55 recommend that before the first chemotherapy, the patient's FN risk should be assessed based on the disease type, chemotherapy regimen, patient risk and treatment purpose. For high-risk groups, G-CSF should be used for prevention. For medium-risk groups, G-CSF should be used for prevention according to the patient's risk. Low-risk groups do not need to use G-CSF for prevention. An evaluation should be performed before each subsequent chemotherapy cycle.

G-CSF mainly acts on HSCs in the G0 phase, promoting their proliferation and differentiation to increase the number of peripheral blood neutrophils [56,57]. The use of G-CSF can significantly reduce the risk of FN [58-61] and the rate of FN-related hospitalization [62]. Prophylactic use of antibiotics is not recommended.

NEW HERB CISTANCHE FOR DEFENSE FUNCTION

2.2 Prevention and treatment of thrombocytopenia

Chemotherapy-related thrombocytopenia may also cause a reduction in the dose of chemotherapy drugs, delay in chemotherapy, or even termination; in addition, thrombocytopenia can lead to bleeding risks, which can even be life-threatening in severe cases [63]. The risk of chemotherapy-induced thrombocytopenia is also related to tumor type, chemotherapy drugs, and regimens. Expert consensus in my country [64] recommends that the risk of thrombocytopenia and bleeding risk should be assessed before chemotherapy based on the patient's condition and chemotherapy regimen. For severe thrombocytopenia, platelet transfusion is the most important treatment measure. Drug treatment can include recombinant human interleukin-11 (rhIL-11) and recombinant human thrombopoietin (rhTPO). Patients with good responses to IL-11 and/or TPO can consider using thrombopoietin receptor agonists. For patients who have experienced ≥ grade 3 thrombocytopenia in the previous cycle of chemotherapy, or who have experienced ≥ grade 2 thrombocytopenia and are also associated with high bleeding risk factors, the preventive use of platelet growth factors is recommended.

NEW HERB CISTANCHE FOR DEFENSE FUNCTION

2.3 Prevention and treatment of anemia

Hemoglobin <11 g/L, or a decrease of >2 g/L from baseline, can be considered anemia [55. There are many causes of chemotherapy-related anemia, including bone marrow suppression caused by chemotherapy. Blood loss, iron deficiency, erythropoietin deficiency, and hormone disorders may also cause anemia[65]. Therefore, it is necessary to identify the anemia from the aspects of cell morphology, reticulocyte count, mean corpuscular volume, etc., and comprehensively analyze the patient's bleeding, hemolysis, nutritional status, genetic factors, renal function, hormone levels and other factors. Treatment should be carried out after the cause of anemia is determined.

3. TCM's understanding of chemotherapy-induced bone marrow suppression

There is no record of "bone marrow suppression" in the classical theory of TCM. However, it is mainly induced by the damage of the viscera and qi by the evil of drug toxicity. According to the clinical manifestations of bone marrow suppression, such as fatigue, decreased immunity, fever, etc., it can be classified into the categories of "deficiency"[66], "deficiency"[67,68], and "blood deficiency"[69]. However, modern physicians have different views on the basic pathogenesis and treatment of chemotherapy-induced bone marrow suppression: Park Bingkui [70] believed that bone marrow suppression was attributed to chemotherapy drugs damaging the spleen and kidney or qi and blood, and that treatment should mainly use products that strengthen the spleen and kidney and replenish qi and blood; Lin Lizhu [71] believed that bone marrow suppression should be treated by replenishing the spleen and kidney and nourishing the liver and kidney; Yang Yufei [66] believed that chemotherapy-induced bone marrow suppression was mainly caused by the weakness of spleen and kidney qi, so replenishing the spleen and kidney was the key to treatment; Fu Huazhou [72] believed that cancer patients had insufficient vital energy, drug toxicity damaged the spleen and stomach, and qi and blood production was insufficient; kidney qi was damaged, and the kidney's function of storing essence and producing marrow was destroyed, causing bone marrow suppression, and spleen and kidney deficiency and qi and blood deficiency were the basic pathogenesis; Lu Su [73] believed that the main pathogenesis of bone marrow suppression caused by chemotherapy of gynecological tumors was that the body's yin and yang were damaged by chemotherapy drugs, and it had nothing to do with qi and blood deficiency; Yao Yang et al. [74] believed that bone marrow suppression caused by chemotherapy of gastric cancer should be diagnosed and treated in stages: prevention before chemotherapy, and regulation of the disease. The main treatment is to strengthen the spleen and stomach, reduce toxicity and increase efficacy during chemotherapy, and strengthen the spleen and kidney. In the late stage of chemotherapy, the main treatment is to prevent the spread of the disease. The treatment should focus on strengthening the spleen and kidney, replenishing essence and nourishing marrow. Li Shanshan et al. [75] based on the theory of zang-fu, believed that the key to chemotherapy-induced bone marrow suppression is spleen and kidney deficiency, and the treatment should focus on replenishing qi and blood, and strengthening the spleen and kidney. Huang Dongrong et al. [76] believed that "hidden poison" damages the spleen and kidney function, leading to bone marrow suppression.

Looking at the understanding of bone marrow suppression by various doctors, although there are differences in qi and blood, yin and yang, etc., their treatment is inseparable from tonifying the spleen and kidney. The spleen is the foundation of the acquired constitution and the source of qi and blood production. "Suwen Linglan Secret Classic" says: "The spleen and stomach are the storehouses", "Lingju Jueqi" says: "The middle burner receives qi and takes juice, which changes and turns red, which is called blood"; the kidney is the foundation of the acquired constitution, responsible for storing essence and producing marrow. "Suwen Yinyang Yingxiang Dalun" says: "The kidney produces bone marrow", "Suwen Qi Tongtian Lun" says: "The bone marrow is strong, and qi and blood follow it". Later works such as Chao Yuanfang's "Zhubingyuanhou Lun", Zhu Tang's "Puji Fang", and Zhang Jingyue's "Jingyue Quanshu" all believe that kidney essence is closely related to the production of qi and blood.

4. The mechanism of Chinese medicine in preventing and treating chemotherapy-induced bone marrow suppression

A large number of studies have shown that Chinese medicine can effectively prevent and treat chemotherapy-induced leukopenia, anemia, thrombocytopenia, etc., and at the same time improve the quality of life of patients [77-86]. A large number of studies have also been conducted on the mechanism of action of Chinese medicine. Traditional Chinese medicine alleviates chemotherapy-induced bone marrow suppression mainly in three aspects: inhibiting HSC apoptosis, delaying HSC aging and regulating HM.

4.1 Inhibiting HSC apoptosis

Zhao et al. [87] found that Liuwei Dihuang Decoction and Buzhong Yiqi Decoction can promote the bone marrow cells of CTX-induced mice from G0 phase to S phase and G2 phase, promote the proliferation of HSCs and HPCs, and inhibit their apoptosis. Danggui Sini Decoction [88] also has the effect of regulating the bone marrow cell cycle and promoting bone marrow cell proliferation. Ming Yue [89] found that Guishao Dihuang Pills can significantly reduce the apoptosis rate of bone marrow nucleated cells in CTX-induced mice, and promote G0/G1 phase cells to enter S phase and G2/M phase. Yu Botao [90] found that Fuzheng Shengxue Capsule prevents and treats CTX-induced bone marrow suppression by upregulating the expression of Bcl-2 and downregulating the expression of Bax. Yang Peiying et al. [91] found that Xiaoyan decoction can promote G0/G1 phase bone marrow cells to enter S and G2/M phases and increase the expression of Bcl-2 mRNA in bone marrow tissue in CTX model mice. Buzhong Yiqi decoction [92] and Taishan Panshi powder [93] have been proven to improve hematopoietic function by relieving the cell cycle arrest of bone marrow hematopoietic cells and promoting proliferation.

In addition, single Chinese medicine/Chinese medicine extracts can also play an anti-apoptotic role in bone marrow cells: ginsenoside Rk3 [941 can reduce the proportion of G0/G1 phase cells in the bone marrow of cyclophosphamide model mice and promote cell proliferation. The mechanism may be related to Rk3 upregulating the expression of Bcl-2 and downregulating the expression of caspase-3. The metabolites of ginsenosides Rb1, Rb2, and Rc and ginsenoside complex K [95] can regulate the proliferation of bone marrow nucleated cells through the Bcl-2/Bax signaling pathway.

4.2 Delay the aging of HSCs

Liuwei Dihuang Pills and Guifu Dihuang Pills [96] can reduce the levels of C and C in mice by increasing superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in myelosuppressed mice. Dialdehyde (malondialdehyde, MDA) plays an anti-oxidative stress role and promotes the recovery of bone marrow hematopoietic function in mice. Guiluerxianjiao [97] can significantly reduce the proportion of aging-related SA-β-gal positive cells in HSCs in CTX model mice and regulate the aging process of HSCs through the p16Ink⁴a-Rb signaling pathway. Angelica sinensis polysaccharides (ASP) can alleviate 5-FU-induced damage to the antioxidant capacity of mouse BMSCs and enhance cellular manganese superoxide dismutase (MnSOD) and catalase (CAT) activity, reducing intracellular reactive oxygen species (ROS) and lipid oxidation marker MDA content [981, reducing the proportion of BMSCs aging-related SA-β-gal positive cells I⁹9], thereby reversing 5-Fu-induced hematopoietic dysfunction. .

4.3 Regulate the hematopoietic microenvironment

Xu Xianguang [100] found in cell experiments that Polygonum multiflorum can alleviate cisplatin-induced damage to BMSCs and alleviate BMSCs apoptosis. Qi Rongjia [98] confirmed in cell experiments that ASP can treat chemotherapy-induced bone marrow suppression by reversing the osteogenic-adipogenic differentiation imbalance of BMSCs and regulating SDF-1. Compound donkey-hide gelatin [101] promotes the recovery of hematopoietic function in myelosuppressed mice by regulating osteogenesis and osteogenic differentiation. Qianggu Shengxue Oral Liquid [53] can upregulate the expression of VEGF and PECAM-1 in the bone marrow tissue of APH and CTX combined model mice, affect the hematopoietic microenvironment, and thus exert a bone marrow protective effect. Danggui Buxue Decoction [102] can increase the expression of TPO and GM-CSF in mice treated with gemcitabine chemotherapy, and plays a role in preventing and treating bone marrow suppression caused by chemotherapy. Ferulic acid, the active ingredient of Angelica sinensis, and astragaloside IV, the active ingredient of Astragalus membranaceus, can increase the content of HGFs in the serum of CTX model mice. The active ingredient Rg1 of Korean ginseng [103] can increase the levels of serum IL-3 and GM-CSF in 5-Fu model mice. It is suggested that Chinese medicine compounds, single Chinese medicines or their active ingredients can promote the recovery of bone marrow hematopoietic function by affecting the hematopoietic microenvironment or hematopoietic growth and regulatory factors in the hematopoietic microenvironment.

5. Summary

The occurrence of myelosuppression is mainly related to the apoptosis, premature aging and HM damage of bone marrow HSCs induced by chemotherapy drugs. Modern medicine can use hematopoietic growth factors to prevent and treat leukopenia, granulocytopenia, anemia and thrombocytopenia caused by chemotherapy. Myelosuppression belongs to the category of fatigue and deficiency in traditional Chinese medicine, and treatment is based on replenishing the spleen and kidneys. Traditional Chinese medicine may play a role by resisting HSCs apoptosis, delaying HSCs senescence and affecting HM.

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