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Gene amplification: a target for cancer therapy
Gene amplification:
a
target for cancer therapy
SiR-Frei (Sept 11, p 662) present an interesting hypothesis that genetic loss of enzymes involved in drug metabolism could result in selective toxicity of cancer chemotherapeutic agents. This possibility would exploit the genetic changes and instability of cancer cells for differential toxicity. Another major type of genetic instability of cancer cells is gene amplification,’ which seems a unique property of cancer cells.2 Because gene amplification is common in most human cancers and the majority of cancers show amplification at one or more loci,3 coamplification is another potential target for therapy. In this case a passenger gene amplified in an amplicon, which may be as large as half a chromosome, would be the candidate drug target: an example is the c-erbB-2 oncogene, which is commonly amplified in human breast cancer. Within the same amplicon, topoisomerase Hot has been shown to be coamplified.4 Since the level of expression of topoisomerase IIa is very important in the activity of a wide range of anticancer drugs (topoisomerase II inhibitors),s high expression from amplified loci may make such tumours more sensitive to chemotherapy. Other candidate genes that could be co-amplified are those involved in activation of antimetabolites such as thymidine kinase, or those involved in drug transport into cells. Alternatively, they may be targets for monoclonal antibodies, if greatly over-expressed compared with normal tissue.6 A better understanding of genes deleted near recessive oncogenes and genes amplified near dominant acting oncogenes may help to develop new tumour-specific therapies.
Adrian L Harris ICRF Clinical
1
2
3 4
5
6
Oncology Unit, Churchill Hospital, Headington, Oxford OX3 7U, UK
Smith KA, Gorman PA, Stack MB, Groves RP, Stark GR. Distinctive chromosomal structures are formed very early in the amplification of CAD genes in Syrian hamster cells. Cell 1990; 63: 1219-27. Wright JA, Smith HS, Watt FM, Hancock MC, Hudson DL, Stark GR. DNA amplification is rare in normal human cells. Proc Natl Acad Sci USA 1990; 87: 1791-95. Alitalo K. Oncogene amplification. Semin Cancer Biol 1993; 4: 1. Smith K, Houlbrook S, Greenall M, Carmichael J, Harris AL. Topoisomerase II&agr; co-amplification with erbB-2 in human primary breast cancer and breast cancer cell lines: relationship to M-AMSA and mitoxantrone sensitivity. Oncogene 1993; 8: 933-38. Liu LF. DNA topoisomerase poisons as antineoplastic drugs. Annu Rev Biochem 1989; 58: 351-75. Curry J, Skandalis A, Holcroft J, Deboer J, Glickman B. Coamplification of hprt cDNA and gamma T-cell receptor sequences from 6-thioguanine resistant human T-lymphocytes. Mutation Res 1993; 288: 269-75.
Immunoglobulin in treatment of Kawasaki syndrome SiR-Lam and colleagues (Sept 11, p 678) suggest that the therapeutic effect of intravenous immunoglobulin in Kawasaki syndrome is mediated by immunomodulatory molecules other than IgG, such as soluble HLA class II and interferon y. This hypothesis contrasts with recent evidence supporting a direct role for IgG in the treatment of Kawasaki syndrome. T cells are divided into families on the basis of the variable region genes expressed in the p chain of their T-cell receptors. During acute Kawasaki syndrome there is a transient rise in Vp2 and Vp8.1 expressing T cells in peripheral blood.1 This rise is similar to the transient increase in Vp2-positive T cells in peripheral blood during staphylococcal toxic shock syndrome. Staphylococcal toxic shock syndrome is caused -by a superantigen-staphylococcal toxic shock syndrome toxin 1.2 Superantigens stimulate specific T-cell families through recognition of their Vp expression. Thus, acute exposure to a superantigen causes an increase in the proportion of peripheral
1172
the Vosequence recognised by that The increase in V02 and Vp8.1 positive T cells superantigen. in peripheral blood in Kawasaki syndrome is strong circumstantial evidence for the involvement of a superantigen. Because pooled human immunoglobulin contains neutralising antibodies to staphylococcal superantigens,3 its therapeutic effect in Kawasaki syndrome is probably mediated by neutralising antibodies to an as yet unidentified microbial
blood T cells
expressing
superantigen. WG
Phillips
St John’s Dermatology Centre, St Thomas’ Hospital, London SE1 7EH, UK
1
2
3
J, Kotzin BL, Jujo K, et al. Selective expansion of T cells expressing T-cell receptor variable regions V&bgr;2 and V&bgr;8 in Kawasaki
Abe
disease. Proc Natl Acad Sci USA 1992; 89: 4066-70. Choi Y, Lafferty JA, Clements JR, et al. Selective expansion of T cells expressing V&bgr;2 in toxic shock syndrome. J Exp Med 1990; 172: 981-84. Takei S, Arora YK, Walker SM. Intravenous immunoglobulin contains specific antibodies inhibitory to activation ofT cells by staphylococcal toxin superantigens. J Clin Invest 1993; 91: 602-07.
Unusual multiresistant Vibrio cholerae 01 El Tor in Argentina SiR-The current South American cholera outbreak, which started in Peru in January, 1991, arrived in our country by February, 1992. Since then, 2072 cases have been reported to national health authorities (451 from Feb 4 to July 24,1992, and 1621 from Sept 16, 1992, to May 29, 1993), with an overall mortality rate below 2 %. Almost 34 % of bacterial isolates were received at the National Reference Laboratory and assessed for toxin production, serotype, and antibiotype. The Ogawa serotype predominated over the Inaba serotype (90-2% for the first outbreak, and 98-3% for the second). All isolates received from the first outbreak (122 strains) were inhibited by low concentrations of first-line antibacterial drugs (minimum inhibitory concentrations [MICs] in mg/L ranging from 2 to 4 for ampicillin, 0 25-0for tetracycline, 0-03-0-6 for co-trimoxazole, 2-4 for erythromycin, 2-8 for nitrofurantoin, and 0007-0015 for norfloxacin) and third-generation cephalosporins, aminoglycosides, and aztreonam. During the following recurrence, an isolate from a female outpatient with moderate dehydration who was treated with single-dose doxicycline by mid-January in Oran, north of Salta Province, showed unusual resistance. This microorganism was only inhibited by 1 mg/L cefotaxime (compared with <0’03 mg/L for all previous isolates), 8 mg/L aztreonam (0-5-1 mg/L previously), 256 mg/L cephalothin (0-5-2), 1024 mg/L ampicillin (2-4), 256 mg/L kanamycin (4-8), and 128 mg/L gentamicin (0-5-2). MICs remained within the expected range for streptomycin, tetracycline, erythromycin, co-trimoxazole, nitrofurantoin, chloramphenicol, and norfloxacin. This strain was confirmed as a toxin-producing Vibrio cholerae 01 biotype El Tor serotype Ogawa, and remained sensitive to the vibriostatic 0129. A crude extract, obtained by sonication of an overnight culture grown at 35°C in brain-heart infusion broth, showed strong beta-lactamase activity on nitrocefin, and when developed after analytical isoelectric focusing with a ceftriaxone/iodometric-based gel overlay, showed an active band with an apparent pI of 8-3. Resistance to ampicillin, aztreonam, cephalothin, cefotaxime, sulphisoxazole, gentamicin, and kanamycin was readily transferred by conjugation to Escherichia coli C600, and from the latter to a susceptible V cholerae. Transferable resistance to third-generation cephalosporins has not been described in this species. Not surprisingly, this antibiotype was found in a country where resistance to
a
target for cancer therapy
SiR-Frei (Sept 11, p 662) present an interesting hypothesis that genetic loss of enzymes involved in drug metabolism could result in selective toxicity of cancer chemotherapeutic agents. This possibility would exploit the genetic changes and instability of cancer cells for differential toxicity. Another major type of genetic instability of cancer cells is gene amplification,’ which seems a unique property of cancer cells.2 Because gene amplification is common in most human cancers and the majority of cancers show amplification at one or more loci,3 coamplification is another potential target for therapy. In this case a passenger gene amplified in an amplicon, which may be as large as half a chromosome, would be the candidate drug target: an example is the c-erbB-2 oncogene, which is commonly amplified in human breast cancer. Within the same amplicon, topoisomerase Hot has been shown to be coamplified.4 Since the level of expression of topoisomerase IIa is very important in the activity of a wide range of anticancer drugs (topoisomerase II inhibitors),s high expression from amplified loci may make such tumours more sensitive to chemotherapy. Other candidate genes that could be co-amplified are those involved in activation of antimetabolites such as thymidine kinase, or those involved in drug transport into cells. Alternatively, they may be targets for monoclonal antibodies, if greatly over-expressed compared with normal tissue.6 A better understanding of genes deleted near recessive oncogenes and genes amplified near dominant acting oncogenes may help to develop new tumour-specific therapies.
Adrian L Harris ICRF Clinical
1
2
3 4
5
6
Oncology Unit, Churchill Hospital, Headington, Oxford OX3 7U, UK
Smith KA, Gorman PA, Stack MB, Groves RP, Stark GR. Distinctive chromosomal structures are formed very early in the amplification of CAD genes in Syrian hamster cells. Cell 1990; 63: 1219-27. Wright JA, Smith HS, Watt FM, Hancock MC, Hudson DL, Stark GR. DNA amplification is rare in normal human cells. Proc Natl Acad Sci USA 1990; 87: 1791-95. Alitalo K. Oncogene amplification. Semin Cancer Biol 1993; 4: 1. Smith K, Houlbrook S, Greenall M, Carmichael J, Harris AL. Topoisomerase II&agr; co-amplification with erbB-2 in human primary breast cancer and breast cancer cell lines: relationship to M-AMSA and mitoxantrone sensitivity. Oncogene 1993; 8: 933-38. Liu LF. DNA topoisomerase poisons as antineoplastic drugs. Annu Rev Biochem 1989; 58: 351-75. Curry J, Skandalis A, Holcroft J, Deboer J, Glickman B. Coamplification of hprt cDNA and gamma T-cell receptor sequences from 6-thioguanine resistant human T-lymphocytes. Mutation Res 1993; 288: 269-75.
Immunoglobulin in treatment of Kawasaki syndrome SiR-Lam and colleagues (Sept 11, p 678) suggest that the therapeutic effect of intravenous immunoglobulin in Kawasaki syndrome is mediated by immunomodulatory molecules other than IgG, such as soluble HLA class II and interferon y. This hypothesis contrasts with recent evidence supporting a direct role for IgG in the treatment of Kawasaki syndrome. T cells are divided into families on the basis of the variable region genes expressed in the p chain of their T-cell receptors. During acute Kawasaki syndrome there is a transient rise in Vp2 and Vp8.1 expressing T cells in peripheral blood.1 This rise is similar to the transient increase in Vp2-positive T cells in peripheral blood during staphylococcal toxic shock syndrome. Staphylococcal toxic shock syndrome is caused -by a superantigen-staphylococcal toxic shock syndrome toxin 1.2 Superantigens stimulate specific T-cell families through recognition of their Vp expression. Thus, acute exposure to a superantigen causes an increase in the proportion of peripheral
1172
the Vosequence recognised by that The increase in V02 and Vp8.1 positive T cells superantigen. in peripheral blood in Kawasaki syndrome is strong circumstantial evidence for the involvement of a superantigen. Because pooled human immunoglobulin contains neutralising antibodies to staphylococcal superantigens,3 its therapeutic effect in Kawasaki syndrome is probably mediated by neutralising antibodies to an as yet unidentified microbial
blood T cells
expressing
superantigen. WG
Phillips
St John’s Dermatology Centre, St Thomas’ Hospital, London SE1 7EH, UK
1
2
3
J, Kotzin BL, Jujo K, et al. Selective expansion of T cells expressing T-cell receptor variable regions V&bgr;2 and V&bgr;8 in Kawasaki
Abe
disease. Proc Natl Acad Sci USA 1992; 89: 4066-70. Choi Y, Lafferty JA, Clements JR, et al. Selective expansion of T cells expressing V&bgr;2 in toxic shock syndrome. J Exp Med 1990; 172: 981-84. Takei S, Arora YK, Walker SM. Intravenous immunoglobulin contains specific antibodies inhibitory to activation ofT cells by staphylococcal toxin superantigens. J Clin Invest 1993; 91: 602-07.
Unusual multiresistant Vibrio cholerae 01 El Tor in Argentina SiR-The current South American cholera outbreak, which started in Peru in January, 1991, arrived in our country by February, 1992. Since then, 2072 cases have been reported to national health authorities (451 from Feb 4 to July 24,1992, and 1621 from Sept 16, 1992, to May 29, 1993), with an overall mortality rate below 2 %. Almost 34 % of bacterial isolates were received at the National Reference Laboratory and assessed for toxin production, serotype, and antibiotype. The Ogawa serotype predominated over the Inaba serotype (90-2% for the first outbreak, and 98-3% for the second). All isolates received from the first outbreak (122 strains) were inhibited by low concentrations of first-line antibacterial drugs (minimum inhibitory concentrations [MICs] in mg/L ranging from 2 to 4 for ampicillin, 0 25-0for tetracycline, 0-03-0-6 for co-trimoxazole, 2-4 for erythromycin, 2-8 for nitrofurantoin, and 0007-0015 for norfloxacin) and third-generation cephalosporins, aminoglycosides, and aztreonam. During the following recurrence, an isolate from a female outpatient with moderate dehydration who was treated with single-dose doxicycline by mid-January in Oran, north of Salta Province, showed unusual resistance. This microorganism was only inhibited by 1 mg/L cefotaxime (compared with <0’03 mg/L for all previous isolates), 8 mg/L aztreonam (0-5-1 mg/L previously), 256 mg/L cephalothin (0-5-2), 1024 mg/L ampicillin (2-4), 256 mg/L kanamycin (4-8), and 128 mg/L gentamicin (0-5-2). MICs remained within the expected range for streptomycin, tetracycline, erythromycin, co-trimoxazole, nitrofurantoin, chloramphenicol, and norfloxacin. This strain was confirmed as a toxin-producing Vibrio cholerae 01 biotype El Tor serotype Ogawa, and remained sensitive to the vibriostatic 0129. A crude extract, obtained by sonication of an overnight culture grown at 35°C in brain-heart infusion broth, showed strong beta-lactamase activity on nitrocefin, and when developed after analytical isoelectric focusing with a ceftriaxone/iodometric-based gel overlay, showed an active band with an apparent pI of 8-3. Resistance to ampicillin, aztreonam, cephalothin, cefotaxime, sulphisoxazole, gentamicin, and kanamycin was readily transferred by conjugation to Escherichia coli C600, and from the latter to a susceptible V cholerae. Transferable resistance to third-generation cephalosporins has not been described in this species. Not surprisingly, this antibiotype was found in a country where resistance to