1.Combination principles of chemotherapy drugs 1.Cell proliferation kinetics 1.Recruitment: for slow growing solid tumors, cell cycle non-specific drugs → cell cycle specific drugs For fast growing tumors (acute leukemia), cell cycle specific drugs → cell cycle non-specific drugs are appropriate 2.Assimilation: cell cycle specific drugs → cell cycle non-specific drugs, firstly, tumor cells are blocked in one primary phase, and then used as drugs for the latter primary phase. After the drug effect disappears, the tumor cells will enter the next cycle synchronously and then be used as the drug for the latter phase. 2. Considering the mechanism of action of drugs, the combined application of drugs acting on different biochemical links can improve the efficacy of the drugs according to the pathogenesis of tumor. Two drugs are used to act on a linear metabolic process at the same time, and two different targets before and after are sequentially inhibited. For example, methotrexate and 6-mercaptopurine. 3, from the consideration of reducing drug toxicity 1, reduce the overlap of toxicity: most antitumor drugs have inhibitory effect on bone marrow, while prednisone and bleomycin have no obvious inhibitory effect on bone marrow, combining them with other drugs to improve the efficacy and reduce the occurrence of bone marrow toxicity. 2.Reduce the toxicity of drugs: Sodium mercaptoethanesulfonate (sodium mesylate) can prevent hemorrhagic cystitis caused by cyclophosphamide Calcium formyl tetrahydrofolate (calcium folinic acid) can reduce the bone marrow toxicity of methotrexate 4.Consider the anti-tumor spectrum of drugs 1. Gastrointestinal cancer: fluorouracil, cyclophosphamide, mitomycin, hydroxyurea 2. Squamous cancer: bleomycin, methotrexate 3. Sarcoma: cyclophosphamide, cisplatin, doxorubicin 4. Osteosarcoma: doxorubicin Osteosarcoma: doxorubicin, high-dose methotrexate (and calcium folinic acid) 5. primary or metastatic tumors of the brain: nitrosoureas, hydroxyurea 5. from reducing the dose of consideration The anti-tumor drugs on the killing of tumor cells follow the principle of first-class kinetics, its anti-tumor effect in a certain dose range has a good dose dependence, beyond this range, can reach the plateau effect, that is, the dose increases, the efficacy does not increase, and the toxic side effects are greatly increased. Toxic side effects are greatly increased. The combination of chemotherapeutic drugs can achieve better efficacy and improve safety with smaller doses. The order of chemotherapy combination 1. Adriamycin first, then paclitaxel: Paclitaxel can destroy the normal division of tumor cells in M phase and G2 phase, while doxorubicin has the strongest effect on cell M phase and S phase. If paclitaxel is used first, it will kill the G2 and M phases, while the S phase will still have tumor cells dividing and coming. On the other hand paclitaxel will reduce adriamycin clearance and increase adriamycin cardiotoxicity and mucositis. 2.Vincristine first, then cyclophosphamide: VCR makes the cells stagnate in M phase and enter G1 phase synchronously after about 6~8h, CTX has the strongest effect on G1 phase cell killing . Combination order: VCR first, CTX after 6~8h. 3.Vincristine first, then bleomycin: Experimental and clinical evidence shows that giving bleomycin after 6h of VCR can significantly improve the efficacy of BLM. 4.Vincristine first, then methotrexate: VCR can block the cells in M phase, which is most significant 6-8h after VCR administration. Therefore, MTX can significantly increase the efficacy 6-8h after VCR administration. On the other hand, VCR can reduce MTX efflux from cells, which has a potentiating effect on MTX. 5. Vincristine first, then menadione: Menadione will reduce the hepatic clearance of vincristine and increase the hepatic and neurotoxicity of vincristine. Therefore, vincristine should be administered 12~24h before menadione. 6.Cyclophosphamide first, then Adriamycin: Cyclophosphamide is a cell cycle non-specific drug, Adriamycin hinders DNA and RNA synthesis, and is most sensitive to S phase, followed by M phase, and less sensitive to G1 phase. 7, first cyclophosphamide, fluorouracil: cyclophosphamide is a cell cycle non-specific drugs, 5-FU is to interfere with the synthesis of DNA and act on S-phase cells. 8.Methotrexate first, then fluorouracil: methotrexate and fluorouracil administered simultaneously or fluorouracil first will produce pharmacological antagonism, but after 4-6h of methotrexate, then fluorouracil can increase the efficacy. 9. Carboplatin first, followed by gemcitabine: 4h of carboplatin followed by gemcitabine will have better efficacy. 10.Cisplatin first, then vincristine: vincristine is a cell cycle specific drug because it blocks microtubule protein polymerization to form microtubules and induces microtubule depolymerization to stop mitosis in the middle of mitosis by blocking microtubule formation. The main target of cisplatin is the DNA of proliferating cells, which causes DNA molecules to cross-bond within and between strands and thus lose their function and fail to replicate, and is a cell cycle non-specific drug. This regimen should be applied with cisplatin first, followed by norviben. 11.Cisplatin first, then fluorouracil: Cisplatin acts on the cell membrane, impeding the entry of exogenous methionine, promoting the production of intracellular methionine, and consequently enhancing the production of active folic acid, and then giving 5-FU, so that it can better play its therapeutic effect. 12.Isocyclophosphamide first, then cisplatin: cisplatin first will aggravate the myelosuppression, neurotoxicity and nephrotoxicity of isocyclophosphamide. 13.Calcium folinic acid first, then fluorouracil: 5-FU is an enzyme that hinders thymine nucleotide synthesis and prevents the synthesis of DNA. This process requires the participation of intracellular active type folate, and the concentration of active type folate in the body is low. If formyl tetrahydrofolate is administered, the concentration of intracellular active type folate can be increased, thus increasing the obstructive effect of 5-FU on DNA synthesis. CF should be used first, followed by 5-FU. peak concentration is reached 2h after intravenous CF and maintained for 2 hours. currently, CF and 5-FU are commonly used alternately in clinical practice, with better results. 14.Iritikant first, then etoposide: If the two are used together, it will show antagonistic effect. Irritikant can increase the content of intracellular topoisomerase-2 mRNA, leading to the overexpression of topoisomerase 2 in tumor cells, and the cytotoxicity of topoisomerase 2 inhibitor (etoposide) is enhanced, so clinically, the use of irritikant is required before etoposide. 15, Etoposide first, then cisplatin: The target of etoposide is DNA topoisomerase II, which inhibits mitosis and stops cell division in S or G2 phase, and is a cell cycle specific drug. Cisplatin is a cell cycle non-specific drug. Paclitaxel first, then platinum agent: When cisplatin is administered before paclitaxel, the mean minimum AUC is greater than the AUC of the opposite order of administration, indicating that the body has a lower clearance of the former condition. Studies of the sequence dependence of paclitaxel and cisplatin co-administration suggest that when drugs that modulate the metabolic effects of or are metabolized by P450 enzymes are used, in combination with paclitaxel, they may cause paclitaxel retention in the body and increase the likelihood of organismal toxicity. Cisplatin has a modulating effect on cytochrome P450 enzymes, reducing the clearance of paclitaxel by 30%.