AntiCancer Inc, San Diego, CA, U.S.A.
Graduate School of Medicine, International University of Health and Welfare, Tokyo, Japan.
In Vivo. 2022 Nov-Dec;36(6):2598-2603. doi: 10.21873/invivo.12994.
BACKGROUND/AIM: Primary osteosarcoma of the mammary gland is a very rare disease, accounting for under 1% of all mammary gland malignancies. There is no established first-line treatment, and prognosis is poor compared to conventional breast cancer. We previously demonstrated the efficacy of cisplatinum and eribulin in a patient-derived orthotopic xenograft (PDOX) mouse model of primary breast osteosarcoma. However, these drugs show significant clinical toxicity. All cancers are addicted to methionine (Hoffman effect). In the present study, we determined whether methionine restriction with oral recombinant methioninase (o-rMETase) would lower the effective dose of cisplatinum in a PDOX model of primary osteosarcoma of the mammary gland, thereby reducing its toxicity.
Mouse PDOX models of primary osteosarcoma of the breast were randomized into the following groups: control; cisplatinum (weekly at 3 or 6 mg/kg); twice-daily o-rMETase; or o-rMETase combined with 3 mg/kg cisplatinum, with treatment for 2 weeks.
Cisplatinum at 6 mg/kg significantly inhibited breast osteosarcoma growth compared with the untreated control and mice treated with 3 mg/kg cisplatinum (p=0.01 and 0.009, respectively). There was no significant difference in tumor growth between mice treated with cisplatinum at 3 mg/kg and the control (p=0.16). Combination therapy with cisplatinum at 3 mg/kg and twice daily o-rMETase regressed the osteosarcoma of the mammary gland (p=0.009), similar to the inhibition by cisplatinum at 6 mg/kg alone. Cisplatinum at 6 mg/kg caused a significant loss of mouse body weight, compared to the control (p=0.02). There was no significant body-weight loss with the combination therapy of o-rMETase and cisplatinum at 3 mg/kg, compared to the untreated control.
o-rMETase halved the effective dose of cisplatinum, thereby eliminating cisplatinum toxicity, demonstrating a future clinical strategy for therapy of osteosarcoma of the breast.
背景/目的：原发性乳腺骨肉瘤是一种非常罕见的疾病，占所有乳腺恶性肿瘤的比例不足 1%。目前尚无标准的一线治疗方法，与常规乳腺癌相比，其预后较差。我们之前在原发性乳腺骨肉瘤的患者来源的原位异种移植（PDOX）小鼠模型中证明了顺铂和艾瑞布林的疗效。然而，这些药物具有明显的临床毒性。所有癌症都依赖于蛋氨酸（Hoffman 效应）。在本研究中，我们确定了在原发性乳腺骨肉瘤的 PDOX 模型中，用口服重组蛋氨酸酶（o-rMETase）进行蛋氨酸限制是否会降低顺铂的有效剂量，从而降低其毒性。
将原发性乳腺骨肉瘤的 PDOX 小鼠模型随机分为以下几组：对照组；顺铂（每周 3 或 6mg/kg）；每日两次 o-rMETase；或 o-rMETase 联合 3mg/kg 顺铂，治疗 2 周。
与未治疗的对照组和用 3mg/kg 顺铂治疗的小鼠相比，6mg/kg 的顺铂显著抑制了乳腺骨肉瘤的生长（p=0.01 和 0.009）。用 3mg/kg 顺铂治疗的小鼠与对照组之间的肿瘤生长无显著差异（p=0.16）。用 3mg/kg 顺铂和每日两次 o-rMETase 联合治疗使乳腺骨肉瘤消退（p=0.009），与单独用 6mg/kg 顺铂抑制效果相似。与对照组相比，6mg/kg 的顺铂导致小鼠体重明显下降（p=0.02）。与未治疗的对照组相比，用 3mg/kg 顺铂和 o-rMETase 联合治疗无明显体重下降。
o-rMETase 将顺铂的有效剂量减半，从而消除了顺铂的毒性，为乳腺癌的治疗提供了未来的临床策略。
