Cytotoxic effect of diphtheria toxin used alone or in combination with other agents on human renal cell carcinoma cell lines

Mizutani, Youichi; Bonavida, Benjamin; Yoshida, Osamu

doi:10.1007/bf00541904

Cited by 6 publications

(3 citation statements)

References 29 publications

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“…This strengthens the argument that ceramide generation contributes to diphtheria toxin toxicity. Because diphtheria toxin also potentiates the cytotoxic effect of TNF-␣, which signals via ceramide, in renal cell carcinoma, 57 ovarian carcinoma, 58 and prostate cancer cells, 59 it has been suggested that the agents share the same pathway of cytotoxicity. 60 We propose that ceramide constitutes an element in the death-signaling cascade initiated by diphtheria toxin and DT 388 -GM-CSF.…”

Section: Discussionmentioning

confidence: 99%

Enhanced ceramide generation and induction of apoptosis in human leukemia cells exposed to DT388–granulocyte-macrophage colony-stimulating factor (GM-CSF), a truncated diphtheria toxin fused to human GM-CSF

Senchenkov

Han

Wang

et al. 2001

Blood

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, a targeted fusion toxin constructed by conjugation of human granulocyte-macrophage colony-stimulating factor (GM-CSF) with the catalytic and translocation domains of diphtheria toxin, is presently in phase I trials for patients with resistant acute myeloid leukemia. HL-60/VCR, a multidrug-resistant human myeloid leukemia cell line, and wild-type HL-60 cells were used to study the impact of DT 388 -GM-CSF on metabolism of ceramide, a modulator of apoptosis. After 48 hours with DT 388 -GM-CSF (10 nM), ceramide levels in HL-60/VCR cells rose 6-fold and viability fell to 10%, whereas GM-CSF alone was without influence.Similar results were obtained in HL-60 cells. Examination of the time course revealed that protein synthesis decreased by about 50% and cellular ceramide levels increased by about 80% between 4 and 6 hours after addition of DT 388 -GM-CSF. By 6 hours this was accompanied by activation of caspase-9, followed by activation of caspase-3, cleavage of caspase substrates, and chromatin fragmentation. Hygromycin B and emetine failed to elevate ceramide levels or induce apoptosis at concentrations that inhibited protein synthesis by 50%. Exposure to C 6 -ceramide inhibited protein synthesis (EC 50 ϳ5 M) and decreased viability (EC 50 ϳ6 M). Sphingomyelinase treatment depleted sphingomyelin by about 10%, while increasing ceramide levels and inhibiting protein synthesis. Diphtheria toxin increased ceramide and decreased sphingomyelin in U-937 cells, a cell line extremely sensitive to diphtheria toxin; exposure to DT 388 -GM-CSF showed sensitivity at less than 1.0 pM. Diphtheria toxin and conjugate trigger ceramide formation that contributes to apoptosis in human leukemia cells through caspase activation and inhibition of protein synthesis. (Blood. 2001; 98:1927-1934

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Section: Discussionmentioning

confidence: 99%

Enhanced ceramide generation and induction of apoptosis in human leukemia cells exposed to DT388–granulocyte-macrophage colony-stimulating factor (GM-CSF), a truncated diphtheria toxin fused to human GM-CSF

Senchenkov

Han

Wang

et al. 2001

Blood

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“…Self-activating retroviral vectors may be useful for development of other suicide genes for cancer therapy. Many suicide genes, such as that for diphtheria toxin or ricin, do not require the presence of a prodrug and may be useful for the treatment of cancers or human immunodeficiency virus type 1 infection (4,13,19,32). However, the toxicity of these genes to the virus producer cells has prevented their development as therapeutic agents.…”

mentioning

confidence: 99%

Psi- vectors: murine leukemia virus-based self-inactivating and self-activating retroviral vectors

Delviks

Pathak

1997

J Virol

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We have developed murine leukemia virus (MLV)-based self-inactivating and self-activating vectors to show that the previously demonstrated high-frequency direct repeat deletions are not unique to spleen necrosis virus (SNV) or the neomycin drug resistance gene. Retroviral vectors pKD-HTTK and pKD-HTpTK containing direct repeats composed of segments of the herpes simplex virus type 1 thymidine kinase (HTK) gene were constructed; in pKD-HTpTK, the direct repeat flanked the MLV packaging signal. The generation of hypoxanthine-aminopterin-thymidine-resistant colonies after one cycle of retroviral replication demonstrated functional reconstitution of the HTK gene. Quantitative Southern analysis indicated that direct repeat deletions occurred in 57 and 91% of the KD-HTTK and KD-HTpTK proviruses, respectively. These results demonstrate that (i) deletion of direct repeats occurs at similar high frequencies in SNV and MLV vectors, (ii) MLV ⌿ can be efficiently deleted by using direct repeats, (iii) suicide genes can be functionally reconstituted during reverse transcription, and (iv) the ⌿ region may be a hot spot for reverse transcriptase template switching events.

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“…Adding TNF-to the existing system was in agreement with supporting evidence of some publications showing a synergistic effect in cell cytotoxicity mediated by TNF-and diphtheria toxin. This was shown on ovarian cancer cell lines-sensitive or resistant to both diphtheria toxin and TNF-and on renal cell carcinoma cell lines (Morimoto et al, 1991, Mizutani et al, 1994. Using a construct in which both TNF-and DTA expressions are driven by H19 tumor specific promoter, would overcome the dose limiting toxic effects of the systemic delivery of TNF-protein.…”

Section: A Single Promoter Driving Two Cytotoxic Genes With Synergistmentioning

confidence: 99%

The H19-IGF2 Role in Bladder Cancer Biology and DNA-Based Therapy

Matouk¹,

Evantal²,

Amit³

et al. 2012

Bladder Cancer - From Basic Science to Robotic Surgery

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Cytotoxic effect of diphtheria toxin used alone or in combination with other agents on human renal cell carcinoma cell lines

Cited by 6 publications

References 29 publications

Enhanced ceramide generation and induction of apoptosis in human leukemia cells exposed to DT388–granulocyte-macrophage colony-stimulating factor (GM-CSF), a truncated diphtheria toxin fused to human GM-CSF

Enhanced ceramide generation and induction of apoptosis in human leukemia cells exposed to DT388–granulocyte-macrophage colony-stimulating factor (GM-CSF), a truncated diphtheria toxin fused to human GM-CSF

Psi- vectors: murine leukemia virus-based self-inactivating and self-activating retroviral vectors

The H19-IGF2 Role in Bladder Cancer Biology and DNA-Based Therapy

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