Raltitrexed as a synergistic hyperthermia chemotherapy drug screened in patient-derived colorectal cancer organoids

Abstract

Objective: Organoids have recently been used as in vitro models to screen chemotherapy drugs in combination with hyperthermia treatment in colorectal cancer. Our research aimed to establish a library of patient-derived colorectal cancer organoids to evaluate synergism between chemotherapy drugs and hyperthermia; validate an index of the hyperthermia chemotherapy sensitization enhancement ratio (HCSER) to identify the chemotherapeutics most enhanced by hyperthermia; and recommend chemotherapy drugs for hyperthermic intraperitoneal treatment. Methods: Organoids were grown from cells extracted from colorectal cancer patient samples or colorectal cancer cell lines. Cells from both sources were encapsulated in 3D Matrigel droplets, which were formulated in microfluidics and phase-transferred into identical cell-laden Matrigel microspheres. The microspheres were seeded in 96-well plates, with each well containing a single microsphere that developed into an organoid after 7 days. The organoids were used to evaluate the efficacy of chemotherapy drugs at both 37 °C as a control and 43 °C for 90 min to examine hyperthermia synergism. Cell viability was counted with 10% CCK8. Results: We successfully established a library of colorectal cancer organoids from 22 patient parental tumors. We examined the hyperthermia synergism of 7 commonly used hyperthermic intraperitoneal chemotherapy drugs. In 11 of the 22 patient organoids, raltitrexed had significant hyperthermia synergism, which was indexed as the highest HCSER score within each patient group. Conclusions: Our results primarily demonstrated the use of patient-derived colorectal cancer organoids as in vitro models to evaluate hyperthermia synergistic chemotherapeutics. We found that hyperthermia enhanced the effect of raltitrexed the most among the common anti-colorectal cancer drugs.

Patient-Derived Organoid Model in the Prediction of Chemotherapeutic Drug Response in Colorectal Cancer

“…It was of paramount importance that PDOs adequately represented the disparate morphologic and histologic characteristics of different CRC subtypes. − The PDOs from different patients showed diversity in growth rate and morphology, and it was essential that PDOs sufficiently represented the diverse histologic features of different cancer subtypes (Figure ). To compare these features of CRC organoids and original CRC tissues, we performed H&E staining and immunohistochemical (IHC) analysis (Figure A).…”

The pivotal application of patient-derived organoid biobanks for personalized treatment of gastrointestinal cancers

“… [ 65 ] CRC Raltitrexed, OXA, MMC, GEM, 5-FU, Lobaplatin, Abraxane CCK-8 Raltitrexed has the most significant hyperthermia synergism among the common hyperthermic intraperitoneal chemotherapy drugs in CRC PDOs. [ 66 ] mCRC 5-FU, OXA, CPT-11 CTG The drug tests based on mCRC PDOs successfully predict the drug response to CPT-11 but fail to predict drug response to 5-FU plus OXA. [ 31 ] mCRC 5-FU, OXA, CPT-11, SN-38 CTG mCRC PDOs show sensitivities to 5-FU, SN-38, the same as drug responses in clinic.…”

“…PDOs could also be applied to detect the combined anti-cancer effect between chemotherapy and other treatment methods. Zeng et al firstly established a library of CRC PDOs from 22 patients to evaluate the combined anti-cancer effect between hyperthermia and chemotherapy drugs [ 66 ]. They found that raltitrexed had the most significant hyperthermia synergism among the 7 common hyperthermic intraperitoneal chemotherapy drugs in CRC PDOs [ 66 ].…”

Living biobank-based cancer organoids: prospects and challenges in cancer research

“…Since Sato et al 6 first generated crypt-villus organoids from Lgr5(+) stem cells, organoid technology has become a promising tool in disease modeling. Many PDOs have been successfully constructed from breast cancer (BC), ovarian cancer (OC) 7 – 9 , lung cancer 10 , gastric cancer (GC) 11 , prostate cancer 12 , bladder cancer (BLC) 13 , liver cancer 14 , esophageal adenocarcinoma (EAC) 15 , pancreatic cancer (PC) 16 , neuroblastoma tumors, glioblastomas 17 , and colorectal cancer (CRC) 18 , 19 . Similarly, in the past 10 years, tumor organoids have become commonly used tools in oncology research ( Table 1 and Figure 1 ), including studies on cancer initiation and progression, preclinical models 20 , explorative and personalized therapies 21 , and drug screening 22 .…”