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Combinatory cytotoxic effects produced by E1B-55kDa-deleted adenoviruses and chemotherapeutic agents are dependent on the agents in esophageal carcinoma.

Ma G, Kawamura K, Li Q, Okamoto S, Suzuki N, Kobayashi H, Liang M, Tada Y, Tatsumi K, Hiroshima K, Shimada H, Tagawa M - Cancer Gene Ther. (2010)

Bottom Line: We also confirmed the antitumor effects by the combination of Ad-delE1B55 with 5-FU in vivo.Cisplatin, however, did not achieve the combinatory effects in most of the cells tested.These data indicate that the Ad-delE1B55 produce combinatory antitumor effects with a chemotherapeutic agent irrespective of the administration schedule, but the effects depend on an agent in esophageal carcinoma.

View Article: PubMed Central - PubMed

Affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan.

ABSTRACT
We examined possible combinatory antitumor effects of replication-competent type 5 adenoviruses (Ad) lacking E1B-55kDa molecules (Ad-delE1B55) and chemotherapeutic agents in nine human esophageal carcinoma cells. Ad-delE1B55 produced cytotoxic effects on all the carcinoma cells and the cytotoxicity is not directly linked with the p53 status of the tumors or with the infectivity to respective tumors. A combinatory treatment with Ad-delE1B55 and an anticancer agent, 5-fluorouracil (5-FU), mitomycin C or etoposide, produced greater cytotoxic effects than that with either the Ad or the agent. Administration of 5-FU could minimally inhibit the viral replication and a simultaneous treatment with the Ad and 5-FU achieved better cytotoxicity than sequential treatments. We also confirmed the antitumor effects by the combination of Ad-delE1B55 with 5-FU in vivo. Cisplatin, however, did not achieve the combinatory effects in most of the cells tested. These data indicate that the Ad-delE1B55 produce combinatory antitumor effects with a chemotherapeutic agent irrespective of the administration schedule, but the effects depend on an agent in esophageal carcinoma.

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Related in: MedlinePlus

(a) Sequential expression of hexon, E1A and GAPDH in TE-11 cells after Ad-delE1B55 infection (MOI=10). (b) Expression of hexon, E1A and GAPDH in TE-11 cells treated with three different schedules. Ad → 5-FU or VP-16, Ad-delE1B55 (MOI=10, day 1) followed by 5-FU (1.25 μ, day 2) or VP-16 (1.25 μ, day 2); 5-FU or VP-16 → Ad, 5-FU or VP-16 (day 1) followed by Ad-delE1B55 (day 2); Ad+5-FU or VP-16, Ad-delE1B55 plus 5-FU or VP-16 at the same time (day 1). The cells treated with the agent only or infected with the Ad only were also tested. Cell lysates were prepared 2 days after Ad-delE1B55 infection. (c) TE-1 or TE-11 cells were treated with Ad-delE1B55 (MOI=10) and/or 5-FU (10 μ) according to the schedule indicated in (b), and cell cycle was analyzed on day 4 (TE-1) or day 6 (TE-11). Respective cell populations showed the average of three samples. (d) Cytotoxic activity of the combination of Ad-delE1B55 (MOI=10) and anticancer agents (5-FU, 10 μ; MMC, 0.625 μ; VP-16, 2.5 μ; CDDP, 10 μ) to TE-1 cells with different treatment schedules. Asterisks show P<0.05.
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fig3: (a) Sequential expression of hexon, E1A and GAPDH in TE-11 cells after Ad-delE1B55 infection (MOI=10). (b) Expression of hexon, E1A and GAPDH in TE-11 cells treated with three different schedules. Ad → 5-FU or VP-16, Ad-delE1B55 (MOI=10, day 1) followed by 5-FU (1.25 μ, day 2) or VP-16 (1.25 μ, day 2); 5-FU or VP-16 → Ad, 5-FU or VP-16 (day 1) followed by Ad-delE1B55 (day 2); Ad+5-FU or VP-16, Ad-delE1B55 plus 5-FU or VP-16 at the same time (day 1). The cells treated with the agent only or infected with the Ad only were also tested. Cell lysates were prepared 2 days after Ad-delE1B55 infection. (c) TE-1 or TE-11 cells were treated with Ad-delE1B55 (MOI=10) and/or 5-FU (10 μ) according to the schedule indicated in (b), and cell cycle was analyzed on day 4 (TE-1) or day 6 (TE-11). Respective cell populations showed the average of three samples. (d) Cytotoxic activity of the combination of Ad-delE1B55 (MOI=10) and anticancer agents (5-FU, 10 μ; MMC, 0.625 μ; VP-16, 2.5 μ; CDDP, 10 μ) to TE-1 cells with different treatment schedules. Asterisks show P<0.05.

Mentions: We first examined whether an anticancer agent influenced the expression levels of viral protein, as the agents inhibit protein synthesis of host cells. We investigated expressions of E1A and hexon proteins, which represent early and late viral gene products, respectively (Figure 3a). E1A protein was produced as early as 12 h after the infection and the production reached to the maximum at 48 h, whereas hexon protein became detectable after 36 h and peaked at 48 h. We then examined the influence of anticancer agents, 5-FU and VP-16, to viral protein synthesis at 48 h in three different administration schedules, Ad administration followed by the agent, the agent followed by Ad and a simultaneous treatment with Ad and the agent (Figure 3b). Production of hexon protein was inhibited by either 5-FU or VP-16 irrespective of the treatment procedures. In contrast, E1A production was downregulated by 5-FU administered before the Ad and by VP-16 after the Ad, but was relatively maintained in other treatment schedules. These data suggest that an anticancer agent suppressed synthesis of viral structure proteins but was less inhibitory to that of viral transcriptional factors. We also examined the p53 expression in TE-11 cells bearing the WT p53 and found that Ad-delE1B55 or 5-FU alone and any combinations did not upregulated p53 (data not shown).


Combinatory cytotoxic effects produced by E1B-55kDa-deleted adenoviruses and chemotherapeutic agents are dependent on the agents in esophageal carcinoma.

Ma G, Kawamura K, Li Q, Okamoto S, Suzuki N, Kobayashi H, Liang M, Tada Y, Tatsumi K, Hiroshima K, Shimada H, Tagawa M - Cancer Gene Ther. (2010)

(a) Sequential expression of hexon, E1A and GAPDH in TE-11 cells after Ad-delE1B55 infection (MOI=10). (b) Expression of hexon, E1A and GAPDH in TE-11 cells treated with three different schedules. Ad → 5-FU or VP-16, Ad-delE1B55 (MOI=10, day 1) followed by 5-FU (1.25 μ, day 2) or VP-16 (1.25 μ, day 2); 5-FU or VP-16 → Ad, 5-FU or VP-16 (day 1) followed by Ad-delE1B55 (day 2); Ad+5-FU or VP-16, Ad-delE1B55 plus 5-FU or VP-16 at the same time (day 1). The cells treated with the agent only or infected with the Ad only were also tested. Cell lysates were prepared 2 days after Ad-delE1B55 infection. (c) TE-1 or TE-11 cells were treated with Ad-delE1B55 (MOI=10) and/or 5-FU (10 μ) according to the schedule indicated in (b), and cell cycle was analyzed on day 4 (TE-1) or day 6 (TE-11). Respective cell populations showed the average of three samples. (d) Cytotoxic activity of the combination of Ad-delE1B55 (MOI=10) and anticancer agents (5-FU, 10 μ; MMC, 0.625 μ; VP-16, 2.5 μ; CDDP, 10 μ) to TE-1 cells with different treatment schedules. Asterisks show P<0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2963731&req=5

fig3: (a) Sequential expression of hexon, E1A and GAPDH in TE-11 cells after Ad-delE1B55 infection (MOI=10). (b) Expression of hexon, E1A and GAPDH in TE-11 cells treated with three different schedules. Ad → 5-FU or VP-16, Ad-delE1B55 (MOI=10, day 1) followed by 5-FU (1.25 μ, day 2) or VP-16 (1.25 μ, day 2); 5-FU or VP-16 → Ad, 5-FU or VP-16 (day 1) followed by Ad-delE1B55 (day 2); Ad+5-FU or VP-16, Ad-delE1B55 plus 5-FU or VP-16 at the same time (day 1). The cells treated with the agent only or infected with the Ad only were also tested. Cell lysates were prepared 2 days after Ad-delE1B55 infection. (c) TE-1 or TE-11 cells were treated with Ad-delE1B55 (MOI=10) and/or 5-FU (10 μ) according to the schedule indicated in (b), and cell cycle was analyzed on day 4 (TE-1) or day 6 (TE-11). Respective cell populations showed the average of three samples. (d) Cytotoxic activity of the combination of Ad-delE1B55 (MOI=10) and anticancer agents (5-FU, 10 μ; MMC, 0.625 μ; VP-16, 2.5 μ; CDDP, 10 μ) to TE-1 cells with different treatment schedules. Asterisks show P<0.05.
Mentions: We first examined whether an anticancer agent influenced the expression levels of viral protein, as the agents inhibit protein synthesis of host cells. We investigated expressions of E1A and hexon proteins, which represent early and late viral gene products, respectively (Figure 3a). E1A protein was produced as early as 12 h after the infection and the production reached to the maximum at 48 h, whereas hexon protein became detectable after 36 h and peaked at 48 h. We then examined the influence of anticancer agents, 5-FU and VP-16, to viral protein synthesis at 48 h in three different administration schedules, Ad administration followed by the agent, the agent followed by Ad and a simultaneous treatment with Ad and the agent (Figure 3b). Production of hexon protein was inhibited by either 5-FU or VP-16 irrespective of the treatment procedures. In contrast, E1A production was downregulated by 5-FU administered before the Ad and by VP-16 after the Ad, but was relatively maintained in other treatment schedules. These data suggest that an anticancer agent suppressed synthesis of viral structure proteins but was less inhibitory to that of viral transcriptional factors. We also examined the p53 expression in TE-11 cells bearing the WT p53 and found that Ad-delE1B55 or 5-FU alone and any combinations did not upregulated p53 (data not shown).

Bottom Line: We also confirmed the antitumor effects by the combination of Ad-delE1B55 with 5-FU in vivo.Cisplatin, however, did not achieve the combinatory effects in most of the cells tested.These data indicate that the Ad-delE1B55 produce combinatory antitumor effects with a chemotherapeutic agent irrespective of the administration schedule, but the effects depend on an agent in esophageal carcinoma.

View Article: PubMed Central - PubMed

Affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan.

ABSTRACT
We examined possible combinatory antitumor effects of replication-competent type 5 adenoviruses (Ad) lacking E1B-55kDa molecules (Ad-delE1B55) and chemotherapeutic agents in nine human esophageal carcinoma cells. Ad-delE1B55 produced cytotoxic effects on all the carcinoma cells and the cytotoxicity is not directly linked with the p53 status of the tumors or with the infectivity to respective tumors. A combinatory treatment with Ad-delE1B55 and an anticancer agent, 5-fluorouracil (5-FU), mitomycin C or etoposide, produced greater cytotoxic effects than that with either the Ad or the agent. Administration of 5-FU could minimally inhibit the viral replication and a simultaneous treatment with the Ad and 5-FU achieved better cytotoxicity than sequential treatments. We also confirmed the antitumor effects by the combination of Ad-delE1B55 with 5-FU in vivo. Cisplatin, however, did not achieve the combinatory effects in most of the cells tested. These data indicate that the Ad-delE1B55 produce combinatory antitumor effects with a chemotherapeutic agent irrespective of the administration schedule, but the effects depend on an agent in esophageal carcinoma.

Show MeSH
Related in: MedlinePlus