Detection of genotoxic substances in cancer patients receiving antineoplastic drugs.

A short-term bacterial mutation test, the SOS Chromotest, has been used to detect the excretion in urine of genotoxic metabolites of antineoplastic drugs administered to cancer patients. In this test, the damage to the DNA of the test bacteria is expressed by the production of beta-galactosidase, which can be quantitatively assessed and is proportional to the concentration of the drug. Kinetic curves of excretion for adriamycin, bleomycin, dacarbazine, cis-platinum and vincristine and their mixtures have been constructed from standard curves relating the intensity of the beta-galactosidase response to the concentration of drugs dissolved in normal urine. Comparative data on extraction and concentration of the drugs from urine or serum by means of selective resin or silica columns are presented.

Synergism between gentamicin and mitomycin C in staphylococcal infections in mice.

Mitomycin C, an antineoplastic antibiotic, and gentamicin showed a dose-related protective effect in mice against a lethal staphylococcal infection when used singly. A combination of these two drugs was shown to be synergistic in the mouse model. A specific logistic regression analysis method confirmed that a synergistic bactericidal effect was obtained with the combination.

Pseudomonas aeruginosa beta-lactamase as a defence against azlocillin, mezlocillin and piperacillin.

Azlocillin, mezlocillin and piperacillin are weak substrates for the chromosomal beta-lactamase of Pseudomonas aeruginosa, and hydrolysis kinetics were calculated. Enzyme function in the living cell was studied by comparing antibiotic activity against a typical Ps. aeruginosa strain with inducible beta-lactamase expression with antibiotic activity against beta-lactamase uninducible and constitutive mutants. The inducible organism was less sensitive than its uninducible mutant to all three agents; this difference was more apparent at high inocula than low and in broth than in agar. These differences involved both enzyme induction and selection of genotypically enzyme derepressed variants. The penicillins were not, however, efficient beta-lactamase inducers at low concentrations and their activity against the inducible organism was antagonized by more potent inducers. Secondary inducers did not antagonize antibiotic activity against beta-lactamase uninducible and constitutive organisms. The beta-lactamase constitutive mutants were highly resistant to the three antibiotics tested.

Bactericidal effect of combinations of antimicrobial drugs and antineoplastic antibiotics against gram-negative bacilli.

Six antineoplastic antibiotics showed little antibacterial activity against 28 strains of four species of gram-negative enteric bacteria. By using the cellophane transfer technique, combinations of these agents with 16 antibacterial drugs usually showed indifference. However, combinations of mitomycin C, especially with the aminoglycosides, were synergistic on strains of Escherichia coli, Proteus, and Klebsiella pneumoniae. Bleomycin, on the other hand, often showed antagonism on strains of E. coli and K. pneumoniae with the beta-lactams, aminoglycosides, and other antibacterial agents. Checkerboard titrations and kinetic killing curves confirmed these findings.

Bactericidal effect of combinations of antimicrobial drugs and antineoplastic antibiotics against Staphylococcus aureus.

Six antineoplastic antibiotics were tested against ten strains of Staphylococcus aureus. Four showed bacteriostatic and/or bactericidal activity against each of the ten strains, and two were only bacteriostatic for seven and nine strains, respectively. Using the cellophane transfer technique, combinations of these antineoplastic antibiotics with 16 antibacterial drugs were screened for combined bactericidal activity. Synergism or antagonism was demonstrated in about one-third of the combinations. Checkerboard titrations and killing curves confirmed these findings and indicated that the effective concentrations of the antibacterial agents were similar to those attainable in the serum after therapeutic doses of these drugs. Although the pharmacokinetics of the six antineoplastic antibiotics in humans are not fully known, at least one of them has a peak serum level corresponding to those values at which a bactericidal effect was produced in vitro.