在基因治療的載體中，以反轉錄病毒最能使外送至細胞內的基因持續而穩定的表現。不過反轉錄病毒感染細胞的能力是取決於其外套膜的特性，所以若能在反轉錄病毒的外套膜上進行修改，使其可以具有專一性地感染特定的細胞，便可用來作為一個腫瘤細胞基因治療的載體。而在反轉錄病毒的外套膜上，先前的研究指出在其上有一proline-rich region (PRR)可以接受一小段胜肽的嵌入，而不會影響病毒顆粒的穩定性，所以修飾外套膜上的PRR來增加病毒和其他的細胞表面受體的結合，進而促使病毒感染其他種類的細胞。在內皮細胞和癌細胞會表現NRP-1(為一個新的VEGF的受體)，而DG-1和DG-2可以專一性地和neuropilin-1 (NRP-1)結合。VEGFR-1在腫瘤的血管新生時扮演著一個重要的角色，而F56可以專一地和VEGFR-1結合並且在動物腫瘤模式中可以有效的抑制腫瘤生長。我們便是分別把DG-1、DG-2、F56這三個胜肽接到病毒的外套膜上。但是研究結果顯示出，在這些改造外套膜的反轉錄病毒似乎不能透過這些受體來感染非老鼠的細胞株或是人類的癌細胞，所以改造反轉錄病毒的外套膜似乎不能改變病毒本身的趨向性。儘管如此，這些在反轉錄病毒的改造外套膜上的胜肽，可以有效地抑制細胞的移動並且可以引響其原來受體的訊息傳導。另外在利用replication- defective的病毒作為基因治療的載體中，有一個很大的限制在於其無法有效率的在活體內傳送治療基因，所以我們構築了一個replication-competent retrovirus (RCR)作為基因的載體，並且也改造其外套膜，我們也證明這些載體可以有效率地在細胞中複製。最後我們在老鼠腫瘤模式中發現這些改造外套膜的RCR載體是可以有效的抑制腫瘤大小。由結果顯示，利用改造外套膜的RCR載體對於腫瘤的治療是有所助益的。

Efficient targeted retroviral gene delivery remains an important goal in gene therapy. The host range of retroviruses is determined primarily by the interaction between the retroviral envelope glycoproteins and specific proteins of the host cell surface that act as retroviral receptors. The variable proline-rich region (PRR) in the retroviral envelope glycoprotein (gp70) has been reported to tolerate a small insertion of peptides, which does not affect the stability of viral particles. The modification of the PRR might redirect binding of the retroviral envelope protein to a new cell surface receptor. We modified the variable PRR of the ecotropic MMLV (Moloney murine leukemia virus) by constructing these peptides (DG-1, DG-2, or F56) to the variable PRR. Peptide DG-1 and DG-2 are composed of 9 amino acids and can specifically bind to neuropilin-1 (NRP-1), a new VEGF receptor, which is expressed by endothelial cells and tumor cells. VEGFR-1/Flt-1 plays important roles during the neovascularization under pathological conditions including tumor. Peptide F56 can specifically bind to VEGF receptor Flt-1 and almost abolished VEGF binding to receptor Flt-1 in vitro. Retroviral vector particles containing such chimeric envelope proteins achieved a wild-type titer on NIH3T3 cells, but the modified retroviruses could not change the tropism to infect non-murine cell lines, such as human lung cancer cells. Therefore, modifications of the envelope on the retroviral vectors might have not redirected the tropism of the retrovirus. Nevertheless, we investigated the functions of these peptides on the modified retroviruses. We found that the DG-1-, DG-2-, or F56-modified retroviruses could inhibit the cell migration and affect the signal transduction of their targeted cells. The modified retroviruses might confer specific binding to the cells and interfere with the functions of targeted receptors. A major obstacle in cancer gene therapy is the limited efficiency of in vivo gene transfer by replication-defective retrovirus vectors in current use. We had also developed replication-competent retroviral (RCR) vectors, derived from the ecotropic MMLV, with DG-1-, DG-2-, or F56-modified envelope. These RCR vectors could stably retain over multiple replication cycles in culture. Finally, these RCR vectors had the antitumor effects in animal tumor models. These result suggested that RCRs with modified envelopes had therapeutic potential for tumors.

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