Purine nucleoside phosphorylases: properties, functions, and clinical aspects.

Doxorubicin (adriamycin) has a very wide antitumour spectrum, compared with other anticancer drugs; however, except for Hodgkin’s disease, it is not associated with curative chemotherapy. Doxorubicin has been in clinical use for more than 2 decades, and only recently has it been recognised that the cytotoxic effect is produced at the cellular level by multiple mechanisms which have not yet been conclusively identified. Key factors are a combination of doxorubicin-induced free radical formation due to metabolic activation, deleterious actions at the level of the membrane, and drug-intercalation into DNA.

Clinical Pharmacokinetics of Doxorubicin

Discovery of podophyllotoxins

We have tested the entire Keio collection of close to 4,000 single-gene knockouts in Escherichia coli for increased susceptibility to one of seven different antibiotics (ciprofloxacin, rifampin, vancomycin, ampicillin, sulfamethoxazole, gentamicin, or metronidazole). We used high-throughput screening of several subinhibitory concentrations of each antibiotic and reduced more than 65,000 data points to a set of 140 strains that display significantly increased sensitivities to at least one of the antibiotics, determining the MIC in each case. These data provide targets for the design of "codrugs" that can potentiate existing antibiotics. We have made a number of double mutants with greatly increased sensitivity to ciprofloxacin, and these overcome the resistance generated by certain gyrA mutations. Many of the gene knockouts in E. coli are hypersensitive to more than one antibiotic. Together, all of these data allow us to outline the cell's "intrinsic resistome," which provides innate resistance to antibiotics.

Determination of Antibiotic Hypersensitivity among 4,000 Single-Gene-Knockout Mutants of Escherichia coli

Chemical and immunological characterization of the 21-kDa ADP-ribosylation factor of adenylate cyclase.

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Robert I. Glazer

Papers

Developments in cancer chemotherapy