Mithramycin (NSC 24559) therapy of testicular tumors

Abstract

A Phase II clinical trial of mithramycin was performed in 99 patients with evaluable metastatic testicular tumors. Patients received 25 μg/kg/day until therapy was stopped because of toxicity. In the absence of persistent toxicity or progression, subsequent courses were begun 4 weeks after discontinuance of the previous course. In the 74 patients with acceptable studies, responses occurred in 26% (5 complete responses and 14 partial responses). Complete responses were persistent for periods of up to 77+ months, and three patients with complete responses were alive and well at last report. Death occurred within 3 weeks after the onset of therapy in 10 patients, and coagulopathy was present in five of these patients. Toxicity of mithramycin was relatively unpredictable, and patients who exhibited severe toxicity received relatively little benefit from therapy. Responses were most common in young men with asymptomatic metastatic disease, and complete responses occurred only in patients with embryonal carcinoma.

Investigations into the sequence-selective binding of mithramycin and related ligands to DNA

“…Mithramycin (Figure 1) is an antitumour antibiotic effective against a wide variety of experimental and human tumours [1]. Although the drug is highly toxic it has proved useful for treating patients with disseminated testicular carcinomas [2][3][4] and Paget's disease [5]. The antibiotic has been shown to inhibit DNA and RNA synthesis in vivo usually with some preference for the latter [6][7][8].…”

Binding of mithramycin to DNA in the presence of second drugs

“…IVlithramycin (MTR) is an antibiotic that contains an aureolic acid group and is closely related to chromomycin A3 and olivomycin. Some studies on this drug, mainly clinical, have been made in recent years (Cause, 1965;Kennedy et al, 1968;Ream et al, 1968;Kennedy, 1970;Hill et al, 1972;Prasad & Nayak, 1976;Dasgupta et al, 1979;Fox & Howarth, 1985). Despite its high toxicity, this drug has proved useful for treating patients with testicular carcinomas (Ream et al, 1968;Kennedy, 1970;Hill et al, 1972) and Paget's disease (Elias et al, 1972).…”

“…Some studies on this drug, mainly clinical, have been made in recent years (Cause, 1965;Kennedy et al, 1968;Ream et al, 1968;Kennedy, 1970;Hill et al, 1972;Prasad & Nayak, 1976;Dasgupta et al, 1979;Fox & Howarth, 1985). Despite its high toxicity, this drug has proved useful for treating patients with testicular carcinomas (Ream et al, 1968;Kennedy, 1970;Hill et al, 1972) and Paget's disease (Elias et al, 1972). MTR inhibits the synthesis of both DNA and RNA in vivo, with some preference for the latter (Kersten et al, 1967;Fok & Waring, 1972).…”

Mithramycin 2′-Oximes with Improved Selectivity, Pharmacokinetics, and Ewing Sarcoma Antitumor Efficacy

“…Yet, despite the success of MTM in preclinical Ewing sarcoma models, a phase I/II clinical trial investigating MTM therapy in children and adults with refractory Ewing sarcoma was recently terminated because of dose-limiting liver toxicity . Similar severe MTM dose-limiting toxicities were observed in previous clinical studies for testicular carcinoma. , Cumulative preclinical and clinical studies also highlighted the poor pharmacokinetics (PK) of MTM as a critical liability that prevents attainment of pharmacologically relevant concentrations in plasma. ,− …”

“…20 Similar severe MTM dose-limiting toxicities were observed in previous clinical studies for testicular carcinoma. 21,22 Cumulative preclinical and clinical studies also highlighted the poor pharmacokinetics (PK) of MTM as a critical liability that prevents attainment of pharmacologically relevant concentrations in plasma. 20,23−25 In an attempt to address the putative off-target activities of MTM that contribute to dose-limiting toxicities, we recently reported strategic modification of MTM C3 aliphatic side chain to afford analogues with improved EWS-FLI1 and Ewing sarcoma cell line selectivity.…”