title: Antitumor sulfonylhydrazines: design, structure-activity relationships, resistance mechanisms, and strategies for improving therapeutic utility.
abstract: 1,2-Bis(sulfonyl)-1-alkylhydrazines (BSHs) were conceived as more specific DNA guanine O-6 methylating and chloroethylating agents lacking many of the undesirable toxicophores contained in antitumor nitrosoureas. O(6)-Alkylguanine-DNA alkyltransferase (MGMT) is the sole repair protein for O(6)-alkylguanine lesions in DNA and has been reported to be absent in 5-20% of most tumor types. Many BSHs exhibit highly selective cytotoxicity toward cells deficient in MGMT activity. The development of clinically useful MGMT assays should permit the identification of tumors with this vulnerability and allow for the preselection of patient subpopulations with a high probability of responding. The BSH system is highly versatile, permitting the synthesis of many prodrug types with the ability to incorporate an additional level of tumor-targeting due to preferential activation by tumor cells. Furthermore, it may be possible to expand the spectrum of activity of these agents to include tumors with MGMT activity by combining them with tumor-targeted MGMT inhibitors.
authors.affiliation: †Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520-8066, United States.
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Shyam
authors.affiliation: †Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520-8066, United States.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Penketh
authors.affiliation: †Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520-8066, United States.
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Baumann
authors.affiliation: ‡Department of Veterinary Sciences, The University of Texas M.D. Anderson Cancer Center, 650 Cool Water Drive, Bastrop, Texas 78602, United States.
authors.forename: Rick A
authors.initials: RA
authors.lastname: Finch
authors.affiliation: †Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520-8066, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhu
authors.affiliation: †Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520-8066, United States.
authors.forename: Yong-Lian
authors.initials: YL
authors.lastname: Zhu
authors.affiliation: †Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520-8066, United States.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Sartorelli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D015687:Cell Hypoxia; D010478:Chemotherapy, Cancer, Regional Perfusion; D003131:Combined Modality Therapy; D015254:DNA Modification Methylases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D006801:Humans; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D057285:Precision Medicine; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D006834:Hydrazines; D013450:Sulfones; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes