Temozolomide regresses a doxorubicin‐resistant undifferentiated spindle‐cell sarcoma patient‐derived orthotopic xenograft (PDOX): precision‐oncology nude‐mouse model matching the patient with effective therapy

Abstract

Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant cancer, resistant to conventional chemotherapy. A patient with high-grade USCS from a striated muscle was implanted orthotopically in the right biceps femoris muscle of mice to establish a patient-derived orthotopic xenograft (PDOX) model. The PDOX models were randomized into the following groups when tumor volume reached 100 mm : G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks); G3, temozolomide (TEM) (25 mg/kg, p.o., daily, for 14 days). Tumor size and body weight were measured with calipers and a digital balance twice a week. TEM significantly inhibited tumor volume growth compared to the untreated control and the DOX-treated group on day 14 after treatment initiation: control (G1): 343 ± 78 mm ; DOX (G2): 308 ± 31 mm , P = 0.272; TEM (G3): 85 ± 21 mm , P < 0.0001. TEM significantly regressed the tumor volume compared to day 0 (P = 0.019). There were no animal deaths in any group. The body weight of treated mice was not significantly different in any group. Tumors treated with DOX were comprised of spindle-shaped viable cells without apparent necrosis or inflammatory changes. In contrast, tumors treated with TEM showed extensive tumor necrosis. The present study demonstrates the potential power of matching the patient with an effective drug and saving the patient needless toxicity from ineffective drugs.

Eribulin Regresses a Doxorubicin-resistant Dedifferentiated Liposarcoma in a Patient-derived Orthotopic Xenograft Mouse Model

“…Using PDOX models, multiple therapeutic agents can be tested (53)(54)(55)(56)(57)(58)(59)(60), including targeted therapy in a preclinical model (61)(62)(63)(64)(65)(66).…”

Current Approaches for Personalized Therapy of Soft Tissue Sarcomas

“…Only a few studies address the optimization of STS treatment. us, the efficacy of temozolomide treatment was demonstrated in the PDX model of doxorubicin-resistant undifferentiated spindle-cell sarcoma [75]. Moreover, Igarashi et al concluded that the PDX model used in the study could identify promising therapies with significantly greater efficacy than first-line therapy for this recalcitrant disease.…”

Pazopanib Inhibits Tumor Growth, Lymph-node Metastasis and Lymphangiogenesis of an Orthotopic Mouse of Colorectal Cancer

“…Athymic nu/nu nude mice (4-6 weeks) were obtained from AntiCancer Inc. Mouse housing, feeding and anesthesia were performed as described in our previous publications (15,16). To minimize any suffering of the animals, anesthesia and analgesics were used for surgical experiments and mice were humanely sacrificed based on methods we have previously published (16,17).…”

“…Mouse housing, feeding and anesthesia were performed as described in our previous publications (15,16). To minimize any suffering of the animals, anesthesia and analgesics were used for surgical experiments and mice were humanely sacrificed based on methods we have previously published (16,17). All animal studies including surgery and imaging were conducted with an AntiCancer, Inc. Institutional Animal Care and Use Committee (IACUC)-protocol specifically approved for this study including surgery and imaging, and in accordance with the principals and procedures outlined in the National Institute of Health Guide for the Care and Use of Animals under Assurance Number A3873-1 (15).…”