Actinomycin D in the treatment of advanced breast cancer

Grimm, Ruby A.; Muss, Hyman B.; White, Dougľas R.; Richards, Frederick; Cooper, M. Robert; Stuart, John J.; Jackson, Don V.; Barnes, Paula L.; Spurr, Charles L.

doi:10.1007/bf00254018

Cited by 10 publications

(10 citation statements)

References 4 publications

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“…That is consistent with an idea that BDNF takes part in sprouting events in epilepsy (17,18). Moreover, in the presented study we used Actinomycin D which has been already in use in treatments of several types of cancer (83)(84)(85). However, in terms of the potential use of Actinomycin D for the treatment of brain diseases including epilepsy, its administration would be challenging due to difficulties of its distribution through the brain-blood barrier (58).…”

Section: Preincubation Of Hippocampal Cultures Withsupporting

confidence: 84%

An important role of the interplay betweenBdnftranscription and histone acetylation in epileptogenesis

Walczak

Czaban

Skupien

et al. 2020

Preprint

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Brain-Derived Neurotrophic Factor is one of the most important trophic proteins in the brain. The role of this growth factor in neuronal plasticity, in health and disease, has been extensively studied. However, mechanisms of epigenetic regulation of Bdnf gene expression in epilepsy are still elusive. In our previous work, using a rat model of neuronal activation upon kainate-induced seizures, we observed a repositioning of Bdnf alleles from the nuclear periphery towards the nuclear center. This change of Bdnf intranuclear position was associated with transcriptional gene activity.In the present study, using the same neuronal activation model, we analyzed the relation between the percentage of the Bdnf allele at the nuclear periphery and clinical and morphological traits of epilepsy. We observed that the decrease of the percentage of the Bdnf allele at the nuclear periphery correlates with stronger mossy fiber sprouting - an aberrant form of excitatory circuits formation. Moreover, using in vitro hippocampal cultures we showed that Bdnf repositioning is a consequence of the transcriptional activity. Inhibition of RNA polymerase II activity in primary cultured neurons with Actinomycin D completely blocked Bdnf gene transcription and repositioning observed after neuronal excitation. Interestingly, we observed that histone deacetylases inhibition with Trichostatin A induced a slight increase of Bdnf gene transcription and its repositioning even in the absence of neuronal excitation. Presented results provide novel insight into the role of BDNF in epileptogenesis. Moreover, they strengthen the statement that this particular gene is a good candidate to search for a new generation of antiepileptic therapies.

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Section: Preincubation Of Hippocampal Cultures Withsupporting

confidence: 84%

An important role of the interplay betweenBdnftranscription and histone acetylation in epileptogenesis

Walczak

Czaban

Skupien

et al. 2020

Preprint

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“…The c-Jun N-terminal kinase (JNK) pathway, which is involved in phosphorylation of c-Jun, is also activated by ActD, which leads to apoptosis (Kleeff, Kornmann, Sawhney, & Korc, 2000). ActD has been used as an experimental drug to treat Wilm's tumor, soft tissue sarcomas, testicular cancer, and lymphomas (Grimm et al, 1980). Parthenolide (PTL), a sesquiterpene lactone, is obtained from few plants (Tanacetum parthenium).…”

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confidence: 99%

Actinomycin‐D and dimethylamino‐parthenolide synergism in treating human pancreatic cancer cells

Lamture

Crooks

Borrelli

2018

Drug Development Research

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Pancreatic cancer is the third leading cause of death in the US with a poor 5-year survival rate of 8.5%. A novel anti-cancer drug, dimethylamino-parthenolide (DMAPT), is the water-soluble analog of the natural sesquiterpene lactone, parthenolide. The putative modes of action of DMAPT are inhibition of the NFκB pathway and depletion of glutathione levels; the latter causing cancer cells to be more susceptible to oxidative stress-induced cell death. Actinomycin-D is a polypeptide antibiotic that binds to DNA and inhibits RNA and protein synthesis by inhibiting RNA polymerase II. A phase 2 clinical trial indicated that Actinomycin-D could be a potent drug against pancreatic cancer; however, it was not a favored drug due to toxicity issues. New drug entities and methods of drug delivery, used alone or in combination, are needed to treat pancreatic cancer more effectively. Thus, it was postulated that combining DMAPT and Actinomycin-D would result in synergistic inhibition of Panc-1 pancreatic cancer cell growth because DMAPT's inhibition of NFκB would enhance induction of apoptosis by Actinomycin-D, via phosphorylation of c-Jun, by minimizing NFκB inhibition of c-Jun phosphorylation. Combining these two drugs induced a higher level of cell death than each drug alone. A fixed drug ratio of DMAPT: Actinomycin-D (1200:1) was used. Data from metabolic (MTT) and colony formation assays were analyzed for synergism with CompuSyn software, which utilizes the Chou-Talalay equation. The analyses indicated synergism and moderate synergism at combination concentrations of DMAPT/Actinomycin-D of 12/0.01 and 18/0.015 µM, respectively.

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“…We document the survival of a child with only minor long-term sequelae following a massive overdose of dactinomycin that was much larger than any previously reported. The most commonly reported toxicities of dactinomycin include mucositis, bone marrow suppression, hepatic dysfunction, and erythematous rashes [1][2][3][4]. These side effects are usually dose-dependent and transient.…”

Section: Discussionmentioning

confidence: 99%

“…

Dactinomycin is an antineoplastic antibiotic used in the treatment of a variety of tumors, including Wilms tumor, soft-tissue sarcomas, testicular cancer, lymphomas, and breast cancer [1][2][3]. The reported extrahematopoetic toxicities are mild and include nausea, vomiting, ulcers of the gastrointestinal mucosa, and elevation of liver enzymes.

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mentioning

confidence: 99%