title: Brostallicin: a new concept in minor groove DNA binder development.
abstract: Brostallicin is a bromoacryloyl derivative of distamycin A, which has shown very promising preclinical activity against a variety of human tumors both in vitro and in vivo. The drug has a limited toxicity towards bone marrow precursor cells in vitro resulting in a therapeutic index much higher than those achieved with other distamycin A derivatives. It retains activity against cancer cells resistant to alkylating agents, topoisomerase I inhibitors and cells with mismatch repair deficiency. Brostallicin has a peculiar mechanism of action involving activation upon binding to glutathione (GSH) catalyzed by glutathione-S-transferase (GST). As a consequence, cells expressing relatively high GST/GSH levels are more susceptible to treatment with brostallicin. Considering that increased levels of GST/GSH are often found in human tumors, this could represent an advantage for the drug in the clinic. Initial clinical studies indicate the tolerability of the drug and allow the determination of the optimal dose for subsequent studies. Some partial response were obtained in these initial phase I studies. Altogether, the results suggest brostallicin to be a new promising anticancer agent with a new mechanism of action. It also raises the possibility to use it in combination with other anticancer drugs currently used.
authors.affiliation: Laboratory of Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. broggini@marionegri.it
authors.forename: Massimo
authors.initials: M
authors.lastname: Broggini
authors.forename: Sergio
authors.initials: S
authors.lastname: Marchini
authors.forename: Erminia
authors.initials: E
authors.lastname: Fontana
authors.forename: Donatella
authors.initials: D
authors.lastname: Moneta
authors.forename: Camilla
authors.initials: C
authors.lastname: Fowst
authors.forename: Cristina
authors.initials: C
authors.lastname: Geroni
mesh_terms: D000477:Alkylating Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D017321:Clinical Trials, Phase I as Topic; D004247:DNA / Q000187:drug effects; D004214:Distamycins / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D005982:Glutathione Transferase / Q000737:chemistry / Q000378:metabolism; D006146:Guanidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D000477:Alkylating Agents; D000970:Antineoplastic Agents; D004214:Distamycins; D004338:Drug Combinations; D006146:Guanidines; D011758:Pyrroles; C030000:stallimycin; D004247:DNA; D005982:Glutathione Transferase; D005978:Glutathione; C455279:brostallicin