Replication-selective herpes simplex virus type 1 mutant therapy of cervical cancer is enhanced by low-dose radiation

被引:55
作者
Blank, SV
Rubin, SC
Coukos, G
Amin, KM
Albelda, SM
Molnar-Kimber, KL
机构
[1] Univ Penn, Med Ctr, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA
[2] Univ Penn, Med Ctr, Dept Surg, Philadelphia, PA 19104 USA
[3] Univ Penn, Med Ctr, Dept Med, Philadelphia, PA 19104 USA
[4] Univ Penn, Med Ctr, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
关键词
D O I
10.1089/10430340252837224
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Herpes simplex virus type 1 (HSV- 1)- based oncolytic treatment is a promising therapeutic approach for malignancy. Recombinant strains of HSV- 1 containing mutations in the ICP 34.5 protein have been shown to replicate preferentially in rapidly proliferating malignant cells, resulting in a direct cytolytic effect. We assessed the efficacy of multimutated HSV- 1 strains on human cervical cancer, and then used these viruses in combination with radiation therapy, the standard treatment for cervical cancer. The HSV- 1 mutants 4009, 7020, 3616, and G207 induced significant lysis of three established human cervical cancer cell lines in vitro in a dose- dependent manner. G207 intratumoral treatment of established subcutaneous C33a tumors in severe combined immunodeficient (SCID) mice significantly reduced tumor burden by 50%. Weekly and triweekly treatments improved efficacy and inhibited flank tumor growth in an administration frequency- dependent manner without toxicity. Combination therapy of a low dose of radiation (1.5 or 3 Gy) and replication- selective HSV mutants infection exhibited increased antitumor effects against cervical cancer cells in vitro. The in vivo effect of G207 combined with low- dose radiation was studied in Me180 xenografts in athymic mice. Treatment of established Me180 tumor nodules with 3 Gy followed by intratumoral G207 administration greatly improved efficacy, resulting in 42% complete eradication of tumor. In conclusion, single and multiple intratumoral injections of G207 significantly reduced tumor burden in xenogeneic models of cervical cancer, and the addition of low- dose radiation further potentiated the effect. These results suggest that replication- selective HSV- 1 mutants may be potent oncolytic agents for the treatment of cervical cancer.
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页码:627 / 639
页数:13
相关论文
共 66 条
  • [1] Advani SJ, 1999, CANCER RES, V59, P2055
  • [2] Enhancement of replication of genetically engineered herpes simplex viruses by ionizing radiation: a new paradigm for destruction of therapeutically intractable tumors
    Advani, SJ
    Sibley, GS
    Song, PY
    Hallahan, DE
    Kataoka, Y
    Roizman, B
    Weichselbaum, RR
    [J]. GENE THERAPY, 1998, 5 (02) : 160 - 165
  • [3] The application of genetically engineered herpes simplex viruses to the treatment of experimental brain tumors
    Andreansky, SS
    He, B
    Gillespie, GY
    Soroceanu, L
    Markert, J
    Chou, J
    Roizman, B
    Whitley, RJ
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (21) : 11313 - 11318
  • [4] Bradley JD, 1999, CLIN CANCER RES, V5, P1517
  • [5] Brinton L A, 1992, IARC Sci Publ, P3
  • [6] EPIDEMIOLOGY OF UTERINE CERVICAL-CANCER
    BRINTON, LA
    FRAUMENI, JF
    [J]. JOURNAL OF CHRONIC DISEASES, 1986, 39 (12): : 1051 - 1065
  • [7] BUDACH W, 1992, CANCER RES, V52, P6292
  • [8] CADOZ M, 1992, 32 INT C ANT AG CHEM
  • [9] Enhancement of gene therapy specificity for diffuse colon carcinoma liver metastases with recombinant herpes simplex virus
    Carroll, NM
    Chiocca, EA
    Takahashi, K
    Tanabe, KK
    [J]. ANNALS OF SURGERY, 1996, 224 (03) : 323 - 329
  • [10] COMPARISON OF GENETICALLY-ENGINEERED HERPES-SIMPLEX VIRUSES FOR THE TREATMENT OF BRAIN-TUMORS IN A SCID MOUSE MODEL OF HUMAN-MALIGNANT GLIOMA
    CHAMBERS, R
    GILLESPIE, GY
    SOROCEANU, L
    ANDREANSKY, S
    CHATTERJEE, S
    CHOU, J
    ROIZMAN, B
    WHITLEY, RJ
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (05) : 1411 - 1415