Arteaga C L, Holt J T
Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Cancer Res. 1996 Mar 1;56(5):1098-1103.
The c-fos proto-oncogene has been implicated as a regulator of estrogen-mediated cell proliferation. We have tested the tissue specificity and antitumor efficacy of a mouse mammary tumor virus-regulated antisense c-fos retroviral vector. Systemically administered vector could be detected in several tissues but was only expressed in breast epithelium, thus supporting targeting to mouse mammary tumor virus-regulated tissues. Ex vivo transduction of 30-70% of MCF-7 human breast cancer cells produced expression of antifos RNA, decreased expression of the c-fos target mRNA, induction of differentiation, and inhibition of s.c. tumor growth and invasiveness. In vivo transduction of established i.p. MCF-7 tumors with a single injection of XM6:antifos inhibited tumor growth in athymic mice with a corresponding inhibition of c-fos, transforming growth factor beta1 and transforming growth factor alpha expression. Four daily injections with the antifos RNA induced a much larger MCF-7 i.p. tumor inhibition, with a marked prolongation of survival in the absence of any host tissue toxicity. These results indicate that inhibition of key nuclear genes such as c-fos may lead to disruption of paracrine factors and an antitumor effect, providing a strategy for cancer gene therapy.
原癌基因c-fos被认为是雌激素介导的细胞增殖的调节因子。我们测试了一种小鼠乳腺肿瘤病毒调节的反义c-fos逆转录病毒载体的组织特异性和抗肿瘤功效。全身给药的载体可在多个组织中检测到，但仅在乳腺上皮中表达，从而支持其靶向小鼠乳腺肿瘤病毒调节的组织。对30%-70%的MCF-7人乳腺癌细胞进行离体转导可产生抗fos RNA的表达，降低c-fos靶mRNA的表达，诱导分化，并抑制皮下肿瘤生长和侵袭。单次注射XM6:抗fos对已建立的腹腔内MCF-7肿瘤进行体内转导可抑制无胸腺小鼠的肿瘤生长，并相应抑制c-fos、转化生长因子β1和转化生长因子α的表达。每天注射4次抗fos RNA可诱导更大程度的腹腔内MCF-7肿瘤抑制，并在无任何宿主组织毒性的情况下显著延长生存期。这些结果表明，抑制关键的核基因如c-fos可能导致旁分泌因子的破坏和抗肿瘤作用，为癌症基因治疗提供了一种策略。
