Hoffman Robert M, Han Qinghong, Kawaguchi Kei, Li Shukuan, Tan Yuying
AntiCancer, Inc., San Diego, CA, USA.
Department of Surgery, University of California, San Diego, CA, USA.
Methods Mol Biol. 2019;1866:311-322. doi: 10.1007/978-1-4939-8796-2_24.
The elevated methionine (MET) requirement of cancer cells is termed MET dependence and is possibly the only known general metabolic defect in cancer. Targeting MET by recombinant methioninase (rMETase) can arrest the growth of cancer cells in vitro and in vivo due to their elevated requirement for MET. rMETase can also potentiate chemotherapy drugs active in S phase due to the selective arrest of cancer cells in S/G phase during MET restriction (MR). We previously reported that rMETase, administrated by intraperitoneal injection (ip-rMETase), could inhibit tumor growth in mouse models of cancer including patient-derived orthotopic xenograft (PDOX) mouse models. We subsequently compared ip-rMETase and oral rMETase (o-rMETase) on a melanoma PDOX mouse model. o-rMETase was significantly more effective than ip-rMETase to inhibit tumor growth without overt toxicity. The combination of o-rMETase+ip-rMETase was significantly more effective than either monotherapy and completely arrested tumor growth. Thus, o-rMETase is effective as an anticancer agent with the potential of clinical development for chronic cancer therapy as well as for cancer prevention. o-rMETase may also have potential as an antiaging agent for healthy people, since MR has been shown to extend the life span of a variety of different organisms.
癌细胞对蛋氨酸（MET）的需求增加被称为MET依赖性，这可能是癌症中唯一已知的普遍代谢缺陷。通过重组蛋氨酸酶（rMETase）靶向MET可以在体外和体内抑制癌细胞的生长，因为它们对MET的需求增加。由于在MET限制（MR）期间癌细胞在S/G期的选择性停滞，rMETase还可以增强在S期具有活性的化疗药物的作用。我们之前报道过，通过腹腔注射给药的rMETase（ip-rMETase）可以抑制癌症小鼠模型中的肿瘤生长，包括患者来源的原位异种移植（PDOX）小鼠模型。我们随后在黑色素瘤PDOX小鼠模型上比较了ip-rMETase和口服rMETase（o-rMETase）。o-rMETase在抑制肿瘤生长方面比ip-rMETase显著更有效，且无明显毒性。o-rMETase + ip-rMETase联合治疗比单一疗法显著更有效，并完全抑制了肿瘤生长。因此，o-rMETase作为一种抗癌剂是有效的，具有用于慢性癌症治疗以及癌症预防的临床开发潜力。o-rMETase对于健康人也可能具有作为抗衰老剂的潜力，因为已经证明MR可以延长多种不同生物体的寿命。
