Trabectedin and irinotecan combination regresses a cisplatinum-resistant osteosarcoma in a patient-derived orthotopic xenograft nude-mouse model
Introduction
Osteosarcoma is the most common primary malignant bone tumor which occurs mainly in children and adolescents [1,2]. Current therapeutic options for osteosarcoma include chemotherapy, surgery, and radiation therapy [3,4]. Cisplatinum (CDDP), doxorubicin (DOX), and high-dose methotrexate (MTX) are usually used either alone or in combination for first-line treatment of osteosarcoma [1,2,5]. However, resistance to these drugs is commonly seen, leading to a recurrence of the tumor which is often fatal to the patient [6]. This suggests that novel strategies are needed to overcome resistance to these drugs.
Trabectedin (TRAB) is an alkylating agent which covalently binds to the minor groove of DNA, disrupting transcription, blocking the cell cycle in late S/G2 phase, leading to apoptosis [7]. TRAB has been used as a single agent for the treatment of patients with soft-tissue sarcoma after failure of DOX or ifosfamide [7].
Irinotecan (IRT), a derivative of camptothecin, is an inhibitor of topoisomerase-1 and prevents DNA replication by binding to the topoisomerase-1-DNA complex, leading cell death in S-phase [8,9]. IRT has been widely used in the treatment of colorectal cancer with limited efficacy and better results have been achieved with IRT in combination with other cytotoxic drugs [10].
A strong synergism of TRAB and IRT has been shown in preclinical reports of several cancers such as Ewing's sarcoma, rhabdomyosarcoma, and ovarian cancer [8,[11], [12], [13]]. However, the efficacy of this combination for osteosarcoma is not known.
In the present study, we determined if the TRAB-IRT combination could overcome CDDP-resistance in a patient-derived orthotopic xenograft (PDOX) models of osteosarcoma.
Section snippets
Mice
Athymic nu/nu nude mice (AntiCancer, Inc., San Diego, CA, USA), 4–6 weeks old, were used. To minimize any suffering of the animals, anesthesia and analgesics were used for all surgical experiments [14]. The mouse investigations presented here were carried out using an AntiCancer, Inc. Institutional Animal Care and Use Committee (IACUC) protocol specifically approved for this study as previously described [14] and as per as the principles and procedures provided in the National Institute of
Efficacy of tested drugs on the osteosarcoma-PDOX
We tested the efficacy of CDDP, TRAB, IRT alone or in combination with TRAB on the CDDP-resistant osteosarcoma in a PDOX mouse model. TRAB alone or IRT alone significantly, but moderately, inhibited osteosarcoma PDOX growth compared with the untreated control (p = 0.04 and p = 0.007, respectively). On the other hand, the TRAB and IRT combination regressed the osteosarcoma PDOX tumor (p < 0.001). Only the TRAB-IRT combination had a significant increased efficacy compared to CDDP (p = 0.02).
Discussion
In the present study, we found the TRAB-IRT combination regressed a chemotherapy-resistant osteosarcoma tumor in a PDOX model (Fig. 4B). This is the first study which shows that the TRAB-IRT combination is active in osteosarcoma.
TRAB exhibited a favorable toxicity profile in the treatment of unrespectable liposarcomas or leiomyosarcomas in the clinic [7]. TRAB inhibited the growth and metastatis of the cutaneous melanoma [17]. TRAB resensitized recurrent ovarian cancer to platinum-based therapy
Declaration of interest statement
AntiCancer Inc. uses PDOX models for contract research. TK, KM, HO, NS, KH, HK, SM, KI and RMH are or were unsalaried associates of AntiCancer Inc. There are no other competing financial interests.
Acknowledgements
This paper is dedicated to the memory of Reese Imhoff.
References (29)
- et al.
Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide
Ann. Oncol.
(2003) - et al.
Synergistic efficacy of irinotecan and sunitinib combination in preclinical models of anaplastic thyroid cancer
Cancer Lett.
(2017) - et al.
Metabolic targeting with recombinant methioninase combined with palbociclib regresses a doxorubicin-resistant dedifferentiated liposarcoma
Biochem. Biophys. Res. Commun.
(2018) - et al.
A patient-derived orthotopic xenograft (PDOX) nude-mouse model precisely identifies effective and ineffective therapies for recurrent leiomyosarcoma
Pharmacol. Res.
(2019) - et al.
Trabectedin and olaparib in patients with advanced and non-resectable bone and soft-tissue sarcomas (TOMAS): an open-label, phase 1b study from the Italian Sarcoma Group
Lancet Oncol.
(2018) - et al.
Trabectedin in combination with doxorubicin for first-line treatment of advanced uterine or soft-tissue leiomyosarcoma (LMS-02): a non-randomised, multicentre, phase 2 trial
Lancet Oncol.
(2015) - et al.
Trabectedin and campthotecin synergistically eliminate cancer stem cells in cell-of-origin sarcoma models
Neoplasia
(2017) Osteosarcoma: review of the past, impact on the future. The American experience
Cancer Treat Res.
(2009)- et al.
Osteosarcoma: a comprehensive review
SICOT J
(2018) - et al.
Current therapeutic strategies and novel approaches in osteosarcoma
Cancers
(2013)
Osteosarcoma: current treatment and a collaborative pathway to success
J. Clin. Oncol.
Prognostic value of histological response to chemotherapy in osteosarcoma patients receiving tumor-bearing frozen autograft
PLoS One
Unique features of trabectedin mechanism of action
Cancer Chemother. Pharmacol.
Combination treatment with trabectedin and irinotecan or topotecan has synergistic effects against ovarian clear cell carcinoma cells
Int. J. Gynecol. Cancer
Cited by (37)
Diterpene promptly executes a non-canonical autophagic cell death in doxorubicin-resistant lung cancer
2022, Biomedicine and PharmacotherapyEffects of trabectedin in the zebrafish Danio rerio: from cells to larvae
2022, Environmental AdvancesCitation Excerpt :Differently from typical DNA-intercalators (e.g. temozolomide and platinum compounds), which are cytotoxic at high concentrations (μg.L−1), trabectedin is active at lower concentrations (ng.L−1 to μg.L−1) (D'Incalci et al., 2014). Ongoing studies and clinical trials have further revealed trabectedin as a promising treatment of other types of tumors, as osteosarcoma and colorectal ones (Higuchi et al., 2019; Jimenez et al., 2020; Zhu et al., 2019). Considering trabectedin's increasing use in treatment schemes, alone and in combination with other AAs in targeted therapies (Gordon et al., 2016), there is a high probability of its presence already occurring in the environment.
Osimertinib regressed an EGFR-mutant lung-adenocarcinoma bone-metastasis mouse model and increased long-term survival
2020, Translational OncologyCitation Excerpt :To minimize any suffering of the animals, anesthesia and analgesics were used for all surgical experiments [10,11]. The mice were observed on a daily basis and humanely sacrificed by over-dosed anesthesia if they met the following humane endpoint criteria: severe tumor burden (more than 20 mm in diameter), prostration, significant body weight loss, difficulty breathing, rotational motion and body temperature drop [10,11]. H1975-RFP cells growing in culture were washed with phosphate-buffered saline (PBS, Mediatech, Inc., Manassas, VA) and harvested by trypsinization.
Combination of oral recombinant methioninase and decitabine arrests a chemotherapy-resistant undifferentiated soft-tissue sarcoma patient-derived orthotopic xenograft mouse model
2020, Biochemical and Biophysical Research CommunicationsCurrent approaches in tissue engineering-based nanotherapeutics for osteosarcoma treatment
2024, Biomedical Materials (Bristol)