Evaluation of the antitumor activity of interleukin-12 in an experimental murine model of colorectal cancer induced by 1,2 dimethylhydrazine (DMH)

Abstract

Objective: interlukin 12 (IL-12) is a cytokine that may enhance the proliferation and cytotoxic activity of T lymphocytes and natural killer (NK) cells. A relationship between extensive intratumoral infiltration of NK cells and longer survival rates in colorectal cancer (CRC) patients was previously noted. Preliminary evidence suggests that the combined administration of IL-12 and IL-2 may produce additive immunomodulatory activity. The purpose of this study was to determine whether the systemic administration of IL-12 (+/-IL-2) may induce an immune response against CRC as induced by 1,2-dimethylhydrazine (DMH).Methods: sixty-five 6-week-old Wistar rats were treated with weekly subcutaneous injections of DMH for 26 weeks at a dose of 20 mg/kg of body weight. Once tumoral induction was over, the animals were randomly allocated to one of three groups: I, control; II, intraperitoneal injections of IL-12; III, intraperitoneal injections of IL-12 combined with IL-2. At 30 weeks, all surviving animals were sacrificed. We studied the following parameters in each rat -number of tumors, size of tumors, and total tumoral volume.Tumor samples were studied using the monoclonal antibody CD 57 for the detection of NK cells. The extent of NK infiltration was classified as small, less than 50 NK cells/50 high-power field (HPF); moderate, 50 to 150 NK cells/50 HPF, and extensive, more than 150 NK cells/50 HPF.Results: thirty-five rats died before completion of the carcinogen exposure, and 30 rats were randomized (10 each group). In group II, 2 animals died during treatment. All rats in groups I and III developed tumors, while in group II two rats (25%) were tumorfree. Moreover, only one rat in group II developed multiple neoplasms, in contrast with group I and group III, where six rats (60%) and seven rats (70%), respectively, had more than one tumor. We found statistically significant differences in the mean number of tumors found in group II when compared to group I (p=0.028) and group III (p = 0.019). Other parameters measured, such as biggest tumor size and total tumoral volume were found to be lower in group II, although no statistical differences were found between groups. Only 10% of rats in group I showed moderated/extensive NK cell infiltration, vs. 60% of rats in group II (p = 0.077) and 70% in group III (p = 0.02).Conclusion: The administration of DMH to rodents provides a reliable and consistent means of inducing CRC that may be suitable for the evaluation of anti-cancer therapies. Our findings suggest that IL-12 is effective against the development of experimental CRC. Its antineoplastic effect could be attributed to the stimulus of this cytokine on the intratumoral infiltration of NK cells.

Preventive Vaccination with Telomerase Controls Tumor Growth in Genetically Engineered and Carcinogen-Induced Mouse Models of Cancer

“…Mice received five weekly DNA injections of the TERT-LTB fusion construct. DMH treatment did not compromise the immune responsiveness in mice (28), and in agreement with previous findings, we found that the immune responsiveness against mTERT [198][199][200][201][202][203][204][205] 6 in DMH treated; n = 6 mice/group).…”

Antitumor Activity of Lentivirus-mediated Interleukin -12 Gene Modified Dendritic Cells in Human Lung Cancer in Vitro

“…Another study showed that dendritic cells pulsed with lung cancer cell lysate could induce tumor specific immune response and showed promising clinical outcomes in patient with lung cancer (Han et al, 2006). The antitumor activity of recombinant IL-12 was tested in a variety of murine tumor models where it causes tumor regression and prolonged the survival of tumor (Coca et al, 2005). Other clinical studies report that the antitumor effect of IL-12 gene-transduced DC vaccine on melanoma, adenocarcinoma of kidney and neuroglioma (Kikuchi et al, 2001;Marten et al, 2003).…”

Experimental Colon Tumorigenesis Induced by 1,2 Dimethylhydrazine in Balb/C Mice

“…Ya pı lan ça lış ma lar da, ko lon kan se ri ge li şi mi ne ek ola rak DMH'nin, hay van lar üze rin de ba zı toksik et ki ler gös ter di ği de ifa de edil miş tir. DMH'nin 20 mg/kg ola rak ve ril di ği bir ça lış ma da, ilk 16 hafta bo yun ca, hay van la rın %53'ünün öl dü ğü ra por edi lir ken 16 ay nı doz ve ri len baş ka bir ça lış ma da, DMH en jek si yo nun dan son ra fark lı za man lar da 210 fa re nin 13 ta ne si nin öl dü ğü be lir til miş tir. 17 Tü mör olu şu mu na bağ lı ola rak ve DMH'nin tüm bu tok sik et ki le rin den do la yı DMH en jek te edi len hay van lar da ki lo kay bı da göz len miş tir.…”