In a period of a little over 20 years, chemotherapy of cancer has evolved from a period of empiricism with little impact on the cancer problem to become part of a sound medical discipline with firm scientific underpinning playing an increasingly important role in the control of cancer. This progress has come from an increasing knowledge of cancer biology and pharmacology and the application of this knowledge to improved design of clinical trials, with due consideration to the intricacies of the natural history of each disease in question. Now that the chemotherapeutic tools are sharpened, their use in combinations with other modalities in the previously unfamiliar setting of the patient with early stages of the disease promises to lead to an even more exciting chapter in clinical cancer research in the next decade.

Combination versus single agent chemotherapy: a review of the basis for selection of drug treatment of cancer.

Chemotherapeutic and antibiotic drugs in the management of infections of the urinary tract.

Streptomycin has been an important drug for the treatment of tuberculosis since its discovery in 1944. But numerous strains of Mycobacterium tuberculosis, the bacterial pathogen that causes tuberculosis, are now streptomycin resistant. Although such resistance is often mediated by mutations within rrs, a 16S rRNA gene or rpsL, which encodes the ribosomal protein S12, these mutations are found in a limited proportion of clinically isolated streptomycin-resistant M. tuberculosis strains. Here we have succeeded in identifying a mutation that confers low-level streptomycin resistance to bacteria, including M. tuberculosis. We found that mutations within the gene gidB confer low-level streptomycin resistance and are an important cause of resistance found in 33% of resistant M. tuberculosis isolates. We further clarified that the gidB gene encodes a conserved 7-methylguanosine (m(7)G) methyltransferase specific for the 16S rRNA, apparently at position G527 located in the so-called 530 loop. Thus, we have identified gidB as a new streptomycin-resistance locus and uncovered a resistance mechanism that is mediated by loss of a conserved m(7)G modification in 16S rRNA. The clinical significance of M. tuberculosis gidB mutation also is noteworthy, as gidB mutations emerge spontaneously at a high frequency of 10(-6) and, once emerged, result in vigorous emergence of high-level streptomycin-resistant mutants at a frequency more than 2000 times greater than that seen in wild-type strains. Further studies on the precise function of GidB may provide a basis for developing strategies to suppress pathogenic bacteria, including M. tuberculosis.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2958.2006.05585.x

Loss of a conserved 7-methylguanosine modification in 16S rRNA confers low-level streptomycin resistance in bacteria.

Ocean viruses alter ecosystems through host mortality, horizontal gene transfer and by facilitating remineralization of limiting nutrients. However, the study of wild viral populations is limited by inefficient and unreliable concentration techniques. Here, we develop a new technique to recover viruses from natural waters using iron-based flocculation and large-pore-size filtration, followed by resuspension of virus-containing precipitates in a pH 6 buffer. Recovered viruses are amenable to gene sequencing, and a variable proportion of phages, depending upon the phage, retain their infectivity when recovered. This Fe-based virus flocculation, filtration and resuspension method (FFR) is efficient (> 90% recovery), reliable, inexpensive and adaptable to many aspects of marine viral ecology and genomics research.

/pdf/a-simple-and-efficient-method-for-concentration-of-ocean-5gm2sximhj.pdf

A simple and efficient method for concentration of ocean viruses by chemical flocculation.

INTEREST in the use of drugs in combination tor the treatment of cancer is not a new phenomenon. It stems from the inability to obtain entirely satisfactory results when available agents are given singly. Theoretical interest in this area can be traced back more than 10 years with the work of Goldin,1 Potter,2 Elion,3 Skipper,4 and Lepage and Sartorelli.5 6 7 The first major clinical effort began in the late 1950's, with the use of drug combinations in the treatment of neoplasms of the testes and other tumors.8 , 9 The current intensity of the interest in this approach derives from two major sources. . . .

The use of drugs in combination for the treatment of cancer: rationale and results.

Recent reports have clearly shown that bacteria tend to become rapidly resistant to streptomycin, both in vitro and clinically (Buggs, Bronstein, Hirshfeld, and Pilling, 1946; Miller and Bohnhoff, 1946; Youmans and Feldman, 1946). In the present work we will report on the development of streptomycin resistance in 12 strains of the shigellae and the nature of this in vitro resistance. A brief summary of this work has previously been reported (Klein and Kimmelman, 1946).

The Role of Spontaneous Variants in the Acquisition of Streptomycin Resistance by the Shigellae.

The problem of drug resistance has become an important limiting factor in the therapeutic efficiency of streptomycin (Buggs et al., 1946; Finland et al., 1946; Bondi et al., 1946). We have previously shown in the case of streptomycin that of 13 strains tested all had the ability to throw off, spontaneously, variants resistant to streptomycin (Klein and Kimmelman, 1946; Klein, 1947). The destruction by streptomycin of the mass of susceptible bacteria and the multiplication of the fe.w highly resistant variants was indicated to be a mechanism for the development of streptomycin resistance. Alexander and Leidy (1947), working with Hemophilus influertae, have recently obtained similar results. Clinically, the inhibition of the rapid development of streptomycin resistance may then require the destruction of a relatively small number of resistant bacteria, which might be effected by the addition of a low concentration of another drug. In the present work we have therefore studied the combined action of streptomycin, penicillin, and sulfadiazine in vitro and determined the relationship between the synergistic action of the compounds and the inhibition of the development of streptomycin resistance.

The Correlation between the Inhibition of Drug Resistance and Synergism in Streptomycin and Penicillin.

The combined action of penicillin and the sulfonamides against bacteria has been demonstrated by several workers. Ungar (1943) reported that penicillin and sulfapyridine showed a marked additive effect both in vitro and in vivo against Staphylococcus aureus and hemolytic streptococci. Soo-Hoo and Schnitzer (1944) reported the additive effect of penicillin when combined with sulfanilamide or sulfapyridine against streptococci. Kirby (1944) using sulfadiazine and Bigger (1944) using sulfathiazole found that these compounds when combined with penicillin showed an additive effect against staphylococci and streptococci. T'ung (1944) found the in vitro sulfathiazole-penicillin combination more efficient than either compound alone when tested against several strains of Brucella. Hobby and Dawson (1944a) found a slight additive effect with sulfapyridine and none with sulfadiazine when these agents were combined with penicillin and tested against staphylococci and streptococci. They also reported that the rate of penicillin activity was reduced when small amounts of the sulfonamides were added. In the present paper we will report on the ability of three sulfonamides (sulfathiazole, sulfadiazine, and sulfapyrazine) to increase the activity of penicillin against ten sulfonamide-susceptible and sulfonamide-resistant strains of S. aureus and eight gram-negative rods. Observations indicating the mechanism of the in vitro additive effect are included in our experimental data.

The Combined Action of Penicillin and the Sulfonamides in Vitro: The Nature of the Reaction.

The theoretical yield of H(2)O(2) formed during the oxidation of a virucidal solution of ascorbic acid approximates the virucidal action of an equivalent amount of H(2)O(2). Both the action of ascorbic acid and H(2)O(2) are completely neutralized by catalase. The action of ascorbic acid against influence A virus may therefore be explained as being due to the H(2)O(2) formed during the Cu catalyzed oxidation of ascorbic acid. The observed in vitro virucidal activity of ascorbic acid obviously can not be utilized therapeutically because of the presence of catalase in body tissues.

The mechanism of the virucidal action of ascorbic acid.

Demerec (1945) and Luria (1946), in studying the resistance of staphylococci to penicillin, found that for a given inoculum (approximately 300,000,000 bacteria) there was a variation in resistance of approximately tenfold for all of their strains; e.g., if the inoculum required 0.1 unit of penicillin for complete inhibition, many of the bacteria in the inoculum would be inhibited by as little as 0.01 unit. The titer of 0.1 unit represented the resistance of a relatively small number of bacteria in the inoculum. Demerec indicated that the development of penicillin resistance resulted from the selection of the most resistant bacteria in concentrations of penicillin not completely inhibiting growth. By continued subcultures in higher penicillin concentrations resistance gradually developed through a series of small increments. We found that, in the case of streptomycin (Klein and Kimmelman, 1946) and penicillin, if one examined only several million bacteria, there was a similar relatively small range of variation in resistance. However, by examining very large numbers of bacteria not previouslyexposed to streptomycin, namely, several billion, it was possible to isolate from all of six strains of the shigellae studied (standard inocula of which were inhibited by 3 to 7 units of streptomycin) variants resistant to more than 1,000 units of streptomycin. The presence of these highly resistant variants (approximately one resistant bacterium to one billion susceptible cells) was indicated to be the critical factor for the very rapid development of streptomycin resistance. Clinically and in vitro (Graessle and Frost, 1946) bacteria become resistant to penicillin at a far slower rate than to streptomycin. If the few highly resistant variants are the factors determining the very rapid development of streptomycin resistance, then it follows that highly resistant variants should regularly be found present in strains showing a rapid rate of development in their streptomycin resistance. Highly resistant penicillin variants should be absent or far less frequent in strains showing a slow rate in their development of penicillin resistance. In the present work we have tested several billion bacteria in each member of a group of strains for the presence of highly resistant variants against penicillin and streptomycin. We have found that while highly resistant variants against streptomycin were present in all the strains tested, no highly resistant variants were found against penicillin. These results were reflected by the rates at which the strains became resistant in vitro to the two chemotherapeutic agents.

Morton Klein

Papers

The Role of Spontaneous Variants in the Acquisition of Streptomycin Resistance by the Shigellae.

The Correlation between the Inhibition of Drug Resistance and Synergism in Streptomycin and Penicillin.

The Combined Action of Penicillin and the Sulfonamides in Vitro: The Nature of the Reaction.

The mechanism of the virucidal action of ascorbic acid.

A Mechanism for the Development of Resistance to Streptomycin and Penicillin.