In vitro- and in vivo-targeted tumor lysis by an MMP2 cleavable melittin-LAP fusion protein.
Chemotherapy is one of the main treatment options for cancer, but the effectiveness of chemotherapeutic drugs is severely limited due to their systemic toxicity. Therefore, the need for a more targeted approach in tumor treatment is obvious. A tumor-activated agent would decrease systemic toxicity as well as increase the efficacy of the treatment. It has previously been shown that the latency of pro-TGF-beta is conferred by dimerization of two latency-associated peptides (LAP) that form a protective shield, which is cleaved off upon activation by matrix metalloproteinases (MMPs). It has also been shown that the fusion of this LAP peptide with other cytokines can confer their latency. In the present study, a recombinant adenovirus with a fusion gene encoding a tumor-activated pro-cytolytic peptide was made in which the LAP domain of TGF-beta was fused with melittin, a potent cytolytic toxin, with an MMP2 cleavage site in between the two. In vitro studies show that the melittin-MMP2-LAP recombinant adenovirus can be activated by MMP2 which leads to the release of free melittin to lyse the target cells. In vivo studies show approximately a 70% decrease in B16 tumor volume in melittin-MMP2-LAP recombinant adenovirus-treated mice as compared to control mice. No significant systemic toxicity was observed in the treated mice.
Holle
Lori
L
Oncology Research Institute of the Greenville Hospital System, Greenville, SC 29605, USA.
Song
Wen
W
Holle
Eric
E
Wei
Yangzhang
Y
Li
Jinhua
J
Wagner
Thomas E
TE
Yu
Xianzhong
X
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016466:CHO Cells; D002470:Cell Survival; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D053779:Latent TGF-beta Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008555:Melitten / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
D053779:Latent TGF-beta Binding Proteins; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D008555:Melitten; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse