The ability of certain antimutagenic agents to prevent development of antibiotic resistance.

Resistance to multiple antimicrobial agents has now become a prominent fact of contemporary life. It is believed that poor patient compliance, e.g. interrupted or premature cessation of therapy; and misuse or abuse of antibiotics, e.g. wrong antibiotic or insufficient dose, play important roles in resistance development. We present evidence that, this form of resistance often stems from spontaneous mutations accompanied by the positive selecting pressure of the doses of antibiotics being between the MIC and MBC levels. A number of antimutagenic agents, e.g. green tea catechins, and other antioxidants, etc. are able to suppress the emergence of resistance. In many cases, these agents are capable of exerting these effects at doses which by themselves produce no visible effect on growth. In a number of cases antimutagenic substances capable of preventing resistance emergence are present in normal food stuffs. These effects are exerted against resistance to tetracyclines, fluoroquinolones, macrolides, beta-lactams, aminoglycosides and the like. The implications of these laboratory findings for practical chemotherapy are discussed.

Role of antimutagens/anticarcinogens in cancer prevention.

Recently it has become increasingly clear that chemicals found in our foods and beverages can prevent the genetic damage that leads to cancer initiation. Such substances may also affect subsequent events in the pathways that lead to cancer, and may have the potential to inhibit the mutations that allow tumor cells to become resistant to antitumor agents. We describe here the antimutagenic potential of Glabrene analogs against EMS-induced mutations utilizing modified Ames tests in S. typhimurium TA 100 and E. coli JC 5088. Results of studies of the ability of well-known antioxidants such as EGCG and related compounds to prevent drug resistance mutations in microorganisms are described, and their possible significance in the prevention of chemotherapeutic drug-resistance in tumor cells is discussed.

Umbelliferone analogues and their potential to inhibit Benzo(a)pyrene- and hydrogen peroxide-induced mutations.

Following the natural product lead, farneciferol-D (kopetdaghin, 8), some ether analogues of umbelliferone were synthesized and assayed for their potential to be antimutagenic/anticarcinogenic against mutations induced by benzo(a)pyrene, a potent mutagen/carcinogen, and hydrogen peroxide, and for their ability to function as free radical scavengers. The "true" antimutagenic effect of these compounds was determined at half the nontoxic concentration in Salmonella typhimurium strains utilizing a modified Ames test protocol, and their free radical-scavenging ability was assayed utilizing a nonenzymatic phenazine methosulfate (PMS)-NADH system. Umbelliferone analogues 4 and 5 demonstrated good potential in preventing mutations induced by benzo(a)pyrene and hydrogen peroxide and also exhibited good superoxide scavenging ability in the PMS-NADH assay, suggesting that the antimutagenic activity of these analogues may be linked to their antioxidative properties.

Antimutagenic/antioxidant activity of green tea components and related compounds.

The ability of green tea components and other antioxidant compounds to function as antimutagens/antioxidants has been well established, and their role in cancer prevention is supported by numerous epidemiological studies. We have utilized modified Ames tests, superoxide scavenging assays, and assays for protection against DNA scissions to compare and contrast the protective effects of various teas and commercial and laboratory-isolated tea components to those produced by compounds such as resveratrol, selenium, curcumin, vitamins C and E, quercetin dihydrate, sulforaphane, ellagic acid dihydrate, glutathione reduced, trolox, butylated hydroxanisole (BHA), butylated hydroxytoluene (BHT), and N-acetyl-L-cysteine (NAC). In Ames tests, employing hydrogen peroxide as a mutagen, epigallocatechin gallate (EGCG) produced the highest level of protection of all antioxidants tested. Measurement of protection against DNA scissions produced results that again showed that EGCG produced the strongest protective effects. In scavenging assays using a xanthine-xanthine oxidase (enzymatic system), epicatechin gallate (ECG) showed the highest scavenging potential. In a nonenzymatic (phenazine methosulfate-NADH) oxidizing system, EGCG once again showed the strongest effects. The implications of these and similar results are discussed in relation to cancer prevention and prevention of drug/antibiotic resistance.