Mithramycin in the Treatment of Disseminated Testicular Neoplasms

Brown, John H.; Kennedy, B. J.

doi:10.1056/nejm196501212720301

Cited by 127 publications

(47 citation statements)

References 5 publications

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“…Quantitative or even temporary remission was confined to a small proportion of the cases selected for study (up to the time of writing). These included cases of malignant changes in both the testis and the ovary and would certainly support the findings of Kofman, Medrek and Alexander (1964) and those of Brown and Kennedy (1965); our impression, therefore, is that Mithramycin may have some specific and beneficial effect on neoplastic changes arising in reproductive tissue. However, we are fully aware that all our patients were in an advanced stage of their disease; the fact that there had been little or no response to previous therapy was a fair indication that dramatic response to yet another cytotoxic agent was only a remote possibility.…”

Section: Discussionsupporting

confidence: 56%

“…Even so, careful assessment of the reports by Kofman and Ream (1963), Spear (1963), and Kofman, Medrek and Alexander (1964) shows that very few cell types and even fewer sites of primary growth are susceptible to cytotoxic activity when treated with Mithramycin. In fact, the only cases in which unequivocal remission has occurred are those of malignant disease of the testis and ovary, which is supported by the trials conducted by Brown and Kennedy (1965).…”

Section: Discussionmentioning

confidence: 87%

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A trial of mithramycin in the treatment of advanced malignant disease.

Sewell¹,

Ellis²

1966

Br J Cancer

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 87%

A trial of mithramycin in the treatment of advanced malignant disease.

Sewell¹,

Ellis²

1966

Br J Cancer

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“…In the present study we showed that mithramycin A, an aureolic acid-type polyketide produced by the soil bacteria S. argillaceus (Jayasuriya et al, 2002), which has been utilized clinically in the US to treat Paget's disease and testicular carcinoma (Brown and Kennedy, 1965;Ryan et al, 1970;Elias and Evans, 1972;, has a dual effect on cells. On the one hand, it strongly activates the p53 tumor suppressor protein by inducing its phosphorylation at Ser 15.…”

Section: Discussionmentioning

confidence: 66%

“…Mithramycin A (also known as aureolic acid, mithracin or plicamycin) is an aureolic acid-type polyketide produced by the soil bacteria Streptomyces argillaceus (Jayasuriya et al, 2002). Mithramycin A inhibits bone resorption by preventing the synthesis of the c-src oncogene in the osteoclast and has been used clinically in the US to treat Paget's disease of the bone and testicular carcinoma (Brown and Kennedy, 1965;Ryan et al, 1970;Elias and Evans, 1972;Hall et al, 1993;Remsing et al, 2003). Mithramycin A is a drug that binds to GC-rich regions in chromatin and interferes with the transcription of genes that bear GC-rich motifs in their promoters (Miller et al, 1987;Ray et al, 1989;Blume et al, 1991;Snyder et al, 1991;Nehls et al, 1993;Aich and Dasgupta, 1995;.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of p53-mediated transcriptional responses by mithramycin A

Koutsodontis

Kardassis

2004

Oncogene

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In the present work, we show that mithramycin A, a drug that is currently used for the treatment of patients with Paget's disease of the bone as well as with several forms of cancer, is a strong activator of the tumor suppressor p53 protein in human hepatoma cells. The time course of p53 activation by mithramycin A was similar to the known chemotherapeutic compound 5-fluorouracil (5-FU). Both 5-FU and mithramycin A induced site-specific phosphorylation of p53 at serine 15. However, in contrast to 5-FU, mithramycin A failed to activate p53 target genes including the cell cycle inhibitor p21 Cip1 gene as well as the proapoptotic genes PUMA (p53-upregulated mediator of apotosis) and BAK (bcl2-homologous antagonist/killer) and blocked the induction of the above genes by 5-FU. Using transactivation assays in Sp1-deficient cells, we showed that mithramycin A inhibited the transcriptional activation of the p21 Cip1 and PUMA promoters by Sp1 and p53. Using chromatin immunoprecipitation assays and a novel protein-protein interaction assay based on biotinylation in vivo, we established that 5-FU enhanced the formation of p53-Sp1 complexes in solution and the subsequent recruitment of both factors to the p21 Cip1 promoter. Mithramycin A also enhanced the recruitment of p53 to the distal p21 Cip1 promoter but totally blocked the recruitment of Sp1 to the proximal p21 Cip1 promoter. Our findings suggest that inhibition of Sp1 binding to the promoters of several p53 target genes, such as the p21 Cip1 gene as well as certain proapoptotic genes, by mithramycin A, prevents the transcriptional induction of these genes by p53 and propose a mechanism that could account for some of the tumor suppressing and antiapoptotic effects of mithramycin A.

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“…The drug acts like Actinomycin D by inhibiting DNA directed DNA synthesis (Yarbro, Kennedy and Barnum, 1966). Its established clinical importance is in the treatment of testicular neoplasms (Kennedy, Griffen and Lober, 1965;Brown and Kennedy, 1965). In addition it has been suggested that the drug may be of value in the emergency treatment of hypercalcaemia (Parsons, Baum and Self, 1967).…”

mentioning

confidence: 99%

Mithramycin Treatment of Hypercalcaemia and Renal Failure in a Patient with Paratesticular Embryonic Sarcoma

Scott¹,

Baum²,

Molland³

et al. 1971

Br J Cancer

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SUMMARY.-A 17-year-old patient with a small paratesticular embryonic sarcoma presented with symptoms of renal failure, polyuria and widespread bone metastases. Investigation revealed hypercalcaemia and uraemia without any evidence of hyperparathyroidism. The hypercalcaemia responded over a period of weeks to administration of mithramycin with initial improvement in the symptoms and metabolic derangements. Control was lost with the necrosis of intra-abdominal tumour deposits and haemorrhagic polypoid deposits in the alimentary tract. The value and hazards of mithramycin are well demonstrated by these rare complications of this type of tumour.

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Mithramycin in the Treatment of Disseminated Testicular Neoplasms

Cited by 127 publications

References 5 publications

A trial of mithramycin in the treatment of advanced malignant disease.

A trial of mithramycin in the treatment of advanced malignant disease.

Inhibition of p53-mediated transcriptional responses by mithramycin A

Mithramycin Treatment of Hypercalcaemia and Renal Failure in a Patient with Paratesticular Embryonic Sarcoma

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