Increased Lifespan of Leukemic Mice Treated with Drugs Related to (–)-Emetine

Jondorf, W. R.; Abbott, B. J.; Greenberg, Nathaniel H.; Mead, J. A. R.

doi:10.1159/000220718

Cited by 25 publications

(15 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In recent years several proteins have been found to possess anti-cancer properties and their possible use in the treatment of human cancer is being explored (Eking and Montgomery, 1979;Griffin et al, 1978;Jondorf et al, 1971;Sawyer et al, 1979). The toxic plant proteins abrin and ricin studied here have little effect on the bone marrow, and are therefore interesting candidates for combination therapy with conventional cytostatic agents having myelosuppression as a dose-limiting side-effect.…”

Section: Discussionmentioning

confidence: 99%

“…We have, therefore, investigated antibody formation against abrin and ricin in treated cancer patients and in mice, using a highly sensitive enzyme-linked immunosorbent assay (ELISA). The results may be of interest also for the use of other foreign proteins with carcinostatic properties (Elting and Montgomery, 1979;Griffin et al, 1978;Jondorf et al, 1971;Sawyer et al, 1979), as well as for the clinical application of monoclonal antibodies, including their use as carriers for toxic proteins such as abrin and ricin or their A-chains (for review see Olsnes and Pihl, 1982b).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Antibody formation against the cytotoxic proteins abrin and ricin in humans and mice

Godal¹,

Fodstad²,

Pihl³

1983

Intl Journal of Cancer

View full text Add to dashboard Cite

Antibody formation may limit the therapeutic use of cancerostatic proteins. To study the significance of antibody formation against abrin and ricin, highly sensitive ELISA procedures for determination of anti-abrin and anti-ricin were developed. In mice treated weekly with therapeutic doses of ricin, antibodies appeared after 2-3 weeks and then rose rapidly, whereas after abrin treatment the antibody formation was slower. Ricin A-chain was found to be more immunogenic than either intact ricin or human serum albumin (HSA). Cyclophosphamide inhibited the antibody response to both abrin and ricin and a combination of cyclophosphamide and prednisolone totally inhibited both anti-abrin and anti-ricin formation during the 6-week observation period. In mice treated weekly with HSA, abrin treatment strongly reduced the anti-HSA formation, showing that abrin has an immunosuppressive effect which appeared to be stronger than that of cyclophosphamide. The existence of circulating antigen-antibody complexes could be demonstrated in the sera of toxin-treated mice by precipitation with polyethyleneglycol, whenever antibodies were detectable with ELISA. The life-span of animals given lethal ricin doses was appreciably enhanced in animals having antibody levels in excess of 10-20 ng/ml. In cancer patients treated i.v. every second week with therapeutic toxin doses, the 10-20 ng/ml levels of anti-ricin and anti-abrin were reached 6-8 weeks and 7-10 weeks after the first injection of ricin and abrin, respectively. The data indicate that the effective therapeutic use of abrin and ricin as single agents may be limited to these time frames, but that the period of effective use may be substantially prolonged if the toxins are given together with conventional cytostatic agents having immuno-suppressive activity.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Antibody formation against the cytotoxic proteins abrin and ricin in humans and mice

Godal¹,

Fodstad²,

Pihl³

1983

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…For determining the life-span of tumour-bearing mice, groups of ten animals were inoculated with Ehrlich ascitesor sarcoma 180-tumour cells as above. Groups other than saline-treated controls received (-)-emetine or (-)-O-methyltubulosine according to dosage schedules based on those found to be optimal for the treatment of mice bearing asciticleukaemia L1210 cells (Jondorf et al, 1971). Animals found dead in the mornings were considered to have survived the previous day for the purpose of calculating mean survival times of the variously treated groups.…”

Section: Methodsmentioning

confidence: 99%

“…Numbers in parenthesis are range of values observed. (Jondorf et al, 1971), are definitely carcinostatic ,but do not completely eradicate Ehrlich ascites or sarcoma 180 cells.…”

Section: Methodsmentioning

confidence: 99%

Some inhibitory effects of (−)-emetine on growth of Ehrlich ascites carcinoma

Johnson

Jondorf

1974

Biochemical Journal

View full text Add to dashboard Cite

(-)-Emetine has little or no effect on O(2) consumption of Ehrlich ascites-cell suspensions or on the viability of transplanted Ehrlich ascites-tumour cells exposed to, or incubated with, the drug in vitro before inoculation into new-host mice. (-)-Emetine administered as a single injection to mice bearing Ehrlich ascites-tumour cells slows the growth rate of the tumour. The subcutaneous or intraperitoneal injection of the drug depresses protein and DNA synthesis of the tumour cells in vivo in a reversible manner. Mice bearing ascitic sarcoma 180 or Ehrlich ascites-tumour cells when given a course of treatment with (-)-emetine or (-)-O-methyltubulosine have a substantially lower tumour load than untreated controls and correspondingly longer survival times.

show abstract

“…As discussed in our earlier study (15), Emetine acts as an effective chemotherapeutic agent by increasing the lifespan of tumor-bearing mice (16,17) and thus has the possibility for clinical advantage (18,19). However, although no previous study explains the mechanism responsible for the anti-tumor effect of Emetine, our results regarding the effects of Emetine on Bcl-x splicing (15) suggested that Emetine promoted the expression of pro-apoptotic proteins by regulating alternative splicing.…”

mentioning

confidence: 93%

Emetine regulates the alternative splicing of caspase 9 in tumor cells

et al. 2011

View full text Add to dashboard Cite

Abstract. Exons 3 to 6 in the caspase 9 gene undergo alternative splicing in which the larger caspase 9 splice variant promotes apoptosis, in contrast to the dominant negative anti-apoptotic splice variant, the smaller caspase 9b. In this study, the regulation of the alternative splicing of caspase 9 pre-mRNA was examined in response to Emetine. Treatment of C33A cells, breast cancer MCF-7 cells and MCF-7/Adr cells with Emetine dihydrochloride upregulated the level of smaller caspase 9b mRNA and concomitantly decreased the mRNA level of larger caspase 9 in a dose-and time-dependent manner, indicating that Emetine desensitizes C33A, MCF-7 and MCF-7/Adr to cell death. In contrast, treatment of PC3 cells, a prostate cancer cell line, manifested an opposite effect: a greater production of the larger caspase 9 mRNA with a concomitant decrease of caspase 9b mRNA. Pretreatment with calyculin A, an inhibitor of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) blocked Emetine-induced alternative splicing in cells, in contrast to okadaic acid, a specific inhibitor of PP2A, demonstrating a PP1-mediated mechanism. These results suggest that the various splicing patterns of the caspase 9 gene that are regulated by chemotherapy reagents may contribute to the resistance or sensitization of the tumors to other cell death inducers.

show abstract

Increased Lifespan of Leukemic Mice Treated with Drugs Related to (–)-Emetine

Cited by 25 publications

References 19 publications

Antibody formation against the cytotoxic proteins abrin and ricin in humans and mice

Antibody formation against the cytotoxic proteins abrin and ricin in humans and mice

Some inhibitory effects of (−)-emetine on growth of Ehrlich ascites carcinoma

Emetine regulates the alternative splicing of caspase 9 in tumor cells

Contact Info

Product

Resources

About