• Modeling Mechanism：

  Semaxinib, as a vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase inhibitor, has the following core mechanism of action: ① It specifically blocks the VEGFR-2 signaling pathway, inhibiting the proliferation, migration, and lumen formation of tumor vascular endothelial cells, thus cutting off tumor blood supply; ② It synergizes with the active metabolite of CPT-11, SN-38: in vitro, it exhibits a synergistic effect on the inhibition of microvascular endothelial cell (HMVEC-d) proliferation (combination index CI < 1), enhancing anti-angiogenic activity by upregulating the expression of the anti-angiogenic factor platelet-reactive protein-1 (TSP-1) and inhibiting Akt phosphorylation; ③ In vivo, it synergizes with metropolitan chemotherapy (low-dose, high-frequency administration) to reduce tumor microvascular density and simultaneously inhibit the growth of colorectal cancer cells (HT-29).

• Related Products：

  Semaxinib (T2064)

• Modeling Method：

  Experimental Subject：

  Mice: CD nu/nu nude mice, male, body weight 20–25 g

  Dosage and Administration Route：

  ① Core modelling (synergistic protocol):
  - Tumour inoculation: Day 0, subcutaneous injection of 1.3×10⁶ HT-29 human colorectal carcinoma cells (0.2 ml serum-free medium) between scapulae;
  - Chemotherapy Intervention: From Day 15 (tumour volume ≈35 mm³), intraperitoneal injection of CPT-11 (cyclic chemotherapy) at 4 mg/kg once daily for 33 days;
  - Targeted combination therapy: Concurrent intraperitoneal injection of Semaxinib at 10 mg/kg;
  - Enhanced regimen (optional): Prior single intraperitoneal injection of CPT-11 at 100 mg/kg (maximum tolerated dose), followed by the aforementioned cyclical chemotherapy+Semaxinib combination regimen for 32 days;
  ② Control treatment:
  - Rhythmic chemotherapy alone group: Intraperitoneal injection of CPT-11 4 mg/kg daily only;
  - Blank control: Intraperitoneal injection of equal volume solvent (saline+99% PEG-300+1% Tween 80)

  Dosing Frequency and Duration Model：

  Semaxinib administered twice weekly for 33 days

• Validation：

  1. Tumor Characteristics: - Growth Inhibition: The combined treatment group (CPT-11 loading dose + metrotherapy + Semaxinib) achieved a tumor volume inhibition rate of 94.5% (T/C value 5.53%), significantly superior to the metrotherapy-only group; - Pathological Morphology: HE staining showed expanded necrotic areas, decreased cell density, and sparse microvessels in the tumor tissue; 2. Vascular Indicators: - Microvessel Density (MVD): CD31 immunohistochemistry showed a significant decrease in tumor MVD in the combined treatment group (84.1% reduction compared to the control group), with disordered vascular structure; - Molecular Indicators: TSP-1 gene expression in tumor tissue was upregulated by 1.95-fold, while VEGF gene expression showed no significant change, consistent with anti-angiogenic characteristics; 3. In Vitro Validation: - Synergistic Inhibition: Semaxinib (0.01-100 μM) combined with SN-38 (1-10000 pM) at a molar ratio of 10000:1 showed 50% inhibition of HMVEC-d cells. The proliferation inhibition concentration was significantly lower than that of the single drug; - Apoptosis induction: the apoptosis rate of endothelial cells was significantly increased after combined treatment, and the proportion of chromatin concentration and nuclear fragmentation increased.

*Precautions： Mice were sacrificed on day 48, and tumor tissue was completely removed.

*References：Bocci G,et,al. Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib. Br J Cancer. 2008 May 20;98(10):1619-29.