完全可以合理推论，伊利替康表柔比星对her2的治疗作用，优于拉帕提尼

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药物都是多靶点的，药物的“常用”靶点未必是它结合亲和力最高的靶点，也未必是它的最佳的靶点；这个靶点之所以成为“常用”，很多时候只不过是因为这个靶点发现的比较早而已。

一、伊立替康

1、伊立替康与her2的结合亲和力，超过拉帕替尼。

《Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2》
HER2-ligand complexes showed that irinotecan (−56.4 ± 5 kcal/mol), quinacrine (−54.9 ± 3 kcal/mol), alfuzosin (−51.9 ± 6 kcal/mol), and antrafenine (−51.1 ± 3 kcal/mol) showed the highest binding free energy for HER2. The affinity of irinotecan and quinacrine was higher than that reported between HER2 and lapatinib (−51 ± 4 kcal/mol) [10] and gefitinib (−26 ± 6.0) .

伊立替康与her2的结合亲和力，超过拉帕替尼。伊立替康是静脉注射药，剂型上也有了脂质体这种比较好的剂型，生物利用度上肯定是超过口服剂型的拉帕替尼的。完全可以合理推论，伊立替康对her2的治疗作用优于拉帕提尼。

2、伊立替康治疗her2的使用场景在于灌注治疗

her2-tki都是口服药；对于her2型的癌性积液胸膜后腹膜后病灶软脑膜病灶等，用腔体灌注的给药方式疗效更好。伊立替康这种能做腔体灌注的注射类药物就有了用武之地。

《伊立替康腹腔灌注治疗癌性腹腔积液的疗效观察》

“对50例癌性腹腔积液的患者,随机分为2组,试验组30例腹腔注入伊立替康40 mg,对照组20例腹腔注入顺铂40 mg+5-氟尿嘧啶1.0 g。”

“伊立替康组完全缓解12例(40%),部分缓解15例(50%),无效3例(10%),总有效率90%;对照组完全缓解5例(25%),部分缓解7例(35%),无效8例(40%),总有效率60%。2组有效率相比有统计学差异(P<0.05)。”

“毒副作用伊利替康组主要表现为第3天短暂轻度腹泻(30%),短暂轻度白细胞下降(20%);对照组副作用主要表现为第2天轻度腹部不适(20%),轻度腹泻(10%)。”

“结论伊立替康40 mg腹腔灌注治疗恶性腹腔积液,疗效显著,毒副作用患者可耐受。”

表柔比星

、表柔比星对her2的结合亲和力高于拉帕替尼

《Radioiodinated Anastrozole and Epirubicin for HER2-Targeted Cancer Therapy: Molecular Docking and Dynamics Insights with Implications for Nuclear Imaging》

This study evaluates radioiodinated anastrozole ([125I]anastrozole) and epirubicin ([125I]epirubicin) for HER2-targeted cancer therapy, utilizing radiopharmaceutical therapy (RPT) for personalized treatment of HER2-positive cancers. Through molecular docking and dynamics simulations (200 ns), it investigates these compounds’ binding affinities and mechanisms to the HER2 receptor compared to lapatinib, a known HER2 inhibitor. Molecular docking studies identified [125I]epirubicin with the highest ΔGbind (−10.92 kcal/mol) compared to lapatinib (−10.65 kcal/mol) and [125I]anastrozole (−9.65 kcal/mol). However, these differences were not statistically significant. Further molecular dynamics (MD) simulations are required to better understand the implications of these findings on the therapeutic potential of the compounds. MD simulations affirmed a stable interaction with the HER2 receptor, indicated by an average RMSD of 4.51 Å for [125I]epirubicin. RMSF analysis pointed to significant flexibility at key receptor regions, enhancing the inhibitory action against HER2. The [125I]epirubicin complex maintained an average of four H-bonds, indicating strong and stable interactions. The average Rg values for [125I]anastrozole and [125I]epirubicin complexes suggest a modest increase in structural flexibility without compromising protein compactness, reflecting their potential to induce necessary conformational changes in the HER2 receptor function. These analyses reveal enhanced flexibility and specific receptor region interactions, suggesting adaptability in binding, which could augment the inhibitory action against HER2. MM-PBSA calculations indicate the potential of these radioiodinated compounds as HER2 inhibitors. Notably, [125I]epirubicin exhibited a free binding energy of −65.81 ± 0.12 kJ/mol, which is comparable to lapatinib at −64.05 ± 0.11 kJ/mol and more favorable than [125I]anastrozole at −57.18 ± 0.12 kJ/mol. The results suggest electrostatic interactions as a major contributor to the binding affinity. The computational analysis underscores that [125I]anastrozole and [125I]epirubicin may have a promising role as HER2 inhibitors, especially [125I]epirubicin due to its high binding affinity and dynamic receptor interactions. These findings, supported by molecular docking scores and MM-PBSA binding energies, advocate for their potential superior inhibitory capability against the HER2 receptor. To validate these computational predictions and evaluate the therapeutic potential of these compounds for HER2-targeted cancer therapy, it is essential to conduct empirical validation through both in vitro and in vivo studies.

二、表柔比星静脉给药，也可腔体注射给药；拉帕替尼口服给药；表柔比星的生物利用度远远大于拉帕替尼。

综上，完全可以合理推论，表柔比星对 her2的疗效优于拉帕替尼。

这实际上也从一个角度上解释了表柔比星的心脏毒性--结合了心肌细胞的her2了--跟曲妥珠的心脏毒性作用机制是一样的。

三、表柔比星治疗her2的运用场景

表柔比星治疗her2的运用场景我觉得主要应该是在腹腔灌注、TACE治疗her2。一般来说治疗腹水、腹腔内病灶、腹膜后病灶、肝病灶才需要用到腹腔灌注、TACE的给药方式。而对于her2型乳腺癌患者来说，出现腹水、腹腔内病灶、腹膜后病灶、肝病灶的时候，曲妥珠、帕妥珠这些注射类的her2抑制剂应该早就耐药了--双妥是her2型的一线靶向药。8201等ADC药物虽然是注射药，但杀伤主要靠后端化疗药，并不是以抑制her2为其主要杀伤机制。

1、表柔比星是能腹腔灌注的

（1）《泵式腹腔灌注5-氟尿嘧啶、表阿霉素、丝裂霉素与43℃蒸馏水对进展期胃癌的意义》

1.2方法胃癌根治术后，立即将F₁型泵式腹腔灌注投药器(苏州市新河卫生器材用品厂生产)的注药塞埋藏于切口旁的皮下，导管端固定于肝圆韧带上，于腹腔内灌入5-Fu 1.5g、E-ADM 60mg、MMC 40mg、43C蒸馏水500ml;保留灌腹，并每隔21天从注药塞处重复应用，连续应用3次。药物注入后，嘱患者反复变动体位，让药液充分分布于腹腔。

（2）《腹腔给药治疗癌性腹水》

1．2 治疗方法常规腹腔抽液600～3000ml‚用卡铂300mg／m2 加生理盐水40ml‚表阿霉素60mg／m2‚加生理盐水40ml 注入腹腔‚化疗后腹水减少或消失者‚生理盐水用量加至200～

2000ml‚嘱患者反复变换体位‚以使药物与腹水充分混合。每周治疗1次‚

2、表柔比星是能TACE的

（1）《肝动脉化疗栓塞治疗巨块型肝癌36例》

常用化疗药为卡铂500mg、5－Fu1000mg、表阿霉素40～60mg。栓塞剂为超液化碘油和表阿霉素的混悬乳剂，依肿瘤的血供情况，决定是否加用明胶海绵颗粒（1～2mm）或明胶海绵条于肿瘤供血动脉主干内行中央型栓塞。 30～45天后依病情重复 T ACE 治疗。

（2）《利多卡因-表阿霉素-超液化碘油混合乳剂在肝癌TACE相关疼痛管理中的应用》

运用最小化法动态随机将患者分为A组（n=28）与B组（n=27）。A组在栓塞前通过导管一次性注入利多卡因100 mg,再注入表阿霉素-超液化碘油乳剂,B组在栓塞术中注入利多卡因-表阿霉素-超液化碘油乳剂。

其中，表阿霉素用量为50 mg／m2(肝功能储备差、高龄或门静脉受肿瘤侵犯的患者适当减量)，超液化碘油用量视肿瘤大小而定，使用总量不超过20 mL。