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Assault against respiratory syncytial virus: beginning of an era
THE LANCET
COMMENTARY without resorting to physical ablation of prion-carrying cells (as in the case of SCID mice)? The normal prion protein, PrPC, may offer an intriguing handle. PrPC is crucial for prion spread within the CNS,9 and it is not unlikely to be required also for spread of prions from peripheral sites to CNS. If the latter suspicion is confirmed, a true opportunity may arise for interference with prion spread and, therefore, for secondary prevention of encephalopathy after exposure to prions. Given the availability of transgenic and knockout mice10,11 for PrPC, answers to these questions should not be far away.
Adriano Aguzzi Department of Pathology, University Hospital, Z urich CH-8091, Switzerland 1
Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science 1982; 216: 136–44. 2 Lasmezas CI, Deslys JP, Robain O, et al. Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science 1997; 275: 402–05. 3 Hill AF, Zeidler M, Ironside J, Collinge J. Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy. Lancet 1997; 349: 99. 4 Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF. Molecular analysis of prion strain variation and the aetiology of “new variant” CJD. Nature 1996; 383: 685–88. 5 Eklund CM, Kennedy RC, Hadlow WJ. Pathogenesis of scrapie virus infection in the mouse. J Infect Dis 1967; 117: 15–22. 6 Muramoto T, Kitamoto T, Hoque MZ, Tateishi J, Goto I. Species barrier prevents an abnormal isoform of prion protein from accumulating in follicular dendritic cells of mice with CreutzfeldtJakob disease. J Virol 1993; 67: 6808–10. 7 Lasmezas CI, Cesbron JY, Deslys JP, et al. Immune system-dependent and independent replication of the scrapie agent. J Virol 1996; 70: 1292–95. 8 Kimberlin RH, Walker CA. Pathogenesis of mouse scrapie: evidence for neural spread of infection to the CNS. J Gen Virol 1980; 51: 183–87. 9 Brandner S, Raeber A, Sailer A, et al. Normal host prion protein (PrPC) required for scrapie spread within the central nervous systme. Proc Natl Acad Sci USA 1996; 93: 13148–51. 10 Bueler H, Aguzzi A, Sailer A, et al. Mice devoid of PrP are resistant to scrapie. Cell 1003; 73: 1339-47. 11 Fischer M, Rulicke T, Raever A, et al. Prion protein (PrP) with aminoproximal deletions restoring susceptibility of PrP knockout mice to scrapie. Embo J 1996: 15: 1255-64.
Assault against respiratory syncytial virus: beginning of an era On the heels of the extraordinary success of effective immunisation against Haemophilus influenzae B, the race for prevention has moved on to another virulent pathogen, respiratory syncytial virus (RSV). Early attempts to conquer RSV with a formalin-inactivated vaccine brought disaster in the form of enhanced infection on exposure to wild virus. Now, more than 25 years later, the first effective prophylactic strategy against RSV has arrived: passive immunisation with a high-titre intravenous immune globulin product, RSV-IGIV. The PREVENT study1 has confirmed the initial report of efficacy of monthly RSV-IGIV infusions during the RSV season,2 prompting approval of RSV-IGIV by the US Food and Drug Administration.3 Most impressive about this well-designed, randomised, double-blind, placebocontrolled trial is its magnitude—54 study centres and 510 patients with clinically significant bronchopulmonary dysplasia and/or extreme prematurity recruited within a 5week period. Evidence of efficacy included significant decreases in hospital admissions and hospital days for RSV infections, in lengthy hospital stays for RSV, and in
Vol 349 • March 15, 1997
admissions for even non-RSV-associated respiratory illnesses. Although it made no impact on intensive-care unit stays, mechanical ventilation requirement, or mortality, prophylactic RSV-IGIV clearly reduced the severity of RSV lower-respiratory-tract infections in highrisk infants, outperforming past trials of ordinary immune globulin.4 Balanced against efficacy are issues of safety, practicality, and cost. A small percentage of treated infants experience adverse events, including respiratory distress, fluid overload, increased diuretic requirement, and difficulties with intravenous access.1,2,4 In addition, in all three randomised trials of RSV-IGIV, there were more deaths in the RSV-IGIV groups than in the control groups.1,2,5 Although not statistically significant, this observation is unexplained and cannot yet be discounted. Nor can the ever-present concern for transmission of unknown infectious agents be summarily dismissed. As for practicality, the regimen for RSV-IGIV is difficult. Even in the controlled setting of a clinical trial, only 82% of participants received >75% of each RSV-IGIV dose.1 The large number of at-risk patients presents both a logistic challenge and the burden of high cost. The one published cost-effectiveness analysis concluded that RSV-IGIV will increase medical costs, but that these expenditures are in line with other commonly used, albeit costly, medical interventions.6 The analysis includes the assumption that RSV-IGIV will save lives, a point that remains to be proven. So, as with any new prophylactic or therapeutic modality, we are left to decide how to incorporate RSVIGIV into our clinical practice. Because of issues of safety, practicality, and cost, it would be prudent to restrict prophylaxis to those at greatest risk.7 For infants with bronchopulmonary dysplasia, severity of RSV infection is most pronounced in children aged <2 years who have required supplementary oxygen in the preceding 6 months, which is also the group of patients with bronchopulmonary dysplasia in whom efficacy of RSVIGIV was shown in the PREVENT trial. For premature infants without lung disease, risk is greatest for those born before <32 weeks’ gestation (before passive transfer of maternal antibody), particularly those ≤6 months of chronological age (and especially those ≤3 months old, for whom efficacy in the PREVENT trial was maximum). A third group at risk from RSV, and for whom use of RSVIGIV would be tempting, are infants with congenital heart disease. However, in the initial RSV-IGIV trial, this subgroup benefited least from RSV-IGIV, and the immune globulin was associated with increased mortality.2 In a subsequent study of infants with congenital heart disease, no overall benefit of RSV-IGIV was observed, and in infants with cyanotic congenital heart disease, RSVIGIV was associated with increased surgical complications and mortality.5 Therefore, because both efficacy and safety are unresolved issues, RSV-IGIV cannot be recommended for children with congenital heart disease. Another group at risk of severe RSV disease are immune deficient patients, particularly those with congenital immune deficiencies and patients receiving chemotherapy or organ transplants. Studies of RSV-IGIV are needed in these patients; until they are done, RSV-IGIV prophylaxis would seem a reasonable empirical intervention during community or nosocomial outbreaks directly threatening 743
THE LANCET
COMMENTARY severely immunocompromised populations. In addition, although in two studies (one in low-risk infants and one in infants who were premature or had bronchopulmonary dysplasia or congenital heart disease) RSV-IGIV was not effective in the treatment of established RSV infections,7 uncontrolled experience at one institution suggested that the combination of high-titre intravenous immune globulin and aerosolised ribavirin might be of therapeutic value in immunocompromised patients.8 The hope is that prophylactic measures against RSV will become simpler and less expensive, thus more broadly applicable—perhaps with monoclonal antibodies and, eventually, active immunisation. RSV-IGIV is a promising first victory; it will probably be only the beginning of the end for RSV.
Such resistance has led many research groups to focus on the molecular pathways of drug resistance, with the aim of developing therapies to defined molecular targets.1 The involvement of the tumour-suppressor gene p53 in DNA repair and apoptosis has led to the suggestion that defects in p53 may determine resistance to chemotherapy.2 Mutations in p53 are the commonest gene mutations observed in human cancer, occurring in approximately 50% of mainly late-stage ovarian tumours.3 Most studies suggest that the presence of a p53 mutation confers a prognostic effect, increasing the aggressiveness of tumours, shortening progression-free intervals, and reducing overall survival rates.4 Many anticancer agents act by inducing apoptosis. Platinum-based drugs (for example, cisplatin) cause DNA damage in dividing cells. When faced with such Mark J Abzug DNA damage, normal cells increase p53 expression and Pediatric Infectious Diseases, University of Colorado School of Medicine respond by either of two pathways. p53 can act to protect and the Children’s Hospital, Denver, Colorado 80218, USA the cell, by halting the cell cycle, thereby allowing the 1 Connor E, Top F, Kramer A, and the PREVENT Study Group. cell to repair the damage. Alternatively, if the damage is Reduction of respiratory syncytial virus hospitalization among too great, the other pathway is initiated, destroying the premature infants and infants with bronchopulmonary dysplasia using damaged cell by apoptosis. The predominant pathway respiratory syncytial virus immune globulin prophylaxis. Pediatrics 1997; 99: 93–99. will depend on the cell type, cellular and molecular 2 Groothuis JR, Simoes EAF, Levin MJ, et al. Prophylactic environment, and degree of DNA damage. Clearly, administration of respiratory syncytial virus immune globulin to highdevising ways to activate only the apoptotic pathway risk infants and young children. N Engl J Med 1993; 329: 1524–30. should lead to better treatment outcome. 3 Nightingale SL. First product available for preventing serious RSV disease. JAMA 1996; 275: 902. What occurs when p53 is absent or is mutated? The 4 Groothuis JR, Simoes EAF, Hemming VG, and the Respiratory tumour cell is unable to undergo p53-mediated cell-cycle Syncytial Virus Immune Globulin Study Group. Respiratory syncytial arrest or apoptosis, which leads to the continued growth virus (RSV) infection in preterm infants and the protective effects of RSV Immune Globulin. Pediatrics 1995; 95: 463–67. of aberrant cells. Laboratory tests on cancer cell-lines in 5 Simoes EAF, Sondheimer HM, Meissner HC, Welliver RC, Groothuis vitro show that mutations in p53 lead to suppression of JR, and the RSVIG Cardiac Study Group. Respiratory syncytial virus the apoptotic pathway, and to chemoresistance. In immunoglobulin as prophylaxis against respiratory syncytial virus in addition, replacing normal p53 function, or stimulating children with congenital heart disease. Pediatr Res 1996; 39: 113A (abstract 662). the apoptotic pathway, leads to the re-establishment of 6 Hay JW, Ernst RL, Meissner HC. Respiratory syncytial virus immune chemosensitivity. In general, tumours with normal p53 globulin: a cost-effectiveness analysis. Am J Man Care 1996; 2: are considered more chemosensitive, whereas tumours 851–61. with mutant p53 are more chemoresistant.5.6 This reflects 7 Meissner HC, Welliver RC, Chartrand SA, Fulton DR, Rodriguez WJA, Groothuis JR. Prevention of respiratory syncytial virus the capability of a particular cell to respond to the DNA infection in high risk infants: consensus opinion on the role of damage by undergoing apoptosis. immunoprophylaxis with respiratory syncytial virus hyperimmune Where does that leave us with expectations for the globulin. Pediatr Infect Dis J 1996; 15: 1059–68. 8 Whimbey E, Champlin RE, Englund JA, et al. Combination therapy future, and will molecular analysis of p53 lead to with aerosolized ribavirin and intravenous immunoglobulin for improved treatment of ovarian cancer? Clearly, the respiratory syncytial virus disease in adult bone marrow transplant determination of p53 mutation status is important in recipients. Bone Marrow Transplant 1995; 16: 393–99. devising the treatment strategy for the ovarian cancer patient, since tumours with p53 mutations would seem to have a worse prognosis and increased Role of p53 in drug resistance in ovarian chemoresistance, requiring aggressive or experimental cancer treatment. The determination of “apoptotic competence” of the tumour cells may be even more The basis of drug resistance in ovarian cancer has been helpful than p53 mutation status as a predictor of the subject of intensive scientific and clinical treatment outcome. In tumours with p53 mutations, investigations over several years. Whilst most ovarian replacement of normal p53 gene by gene therapy, or cancer patients will initially respond to non-specific treatment with apoptosis-regulating molecules may be chemotherapy, such as cisplatin, only a minority will be successful strategies. In addition, the use of drug cured, because of innate or acquired drug resistance. treatments that do not require Exploiting p53 in drug response by ovarian cancer p53-dependent apoptosis, such as paclitaxel, may help Chemosensitive tumour Chemoresistant tumour Potential therapy overcome resistance,7 and Chemotherapy Chemotherapy Chemotherapy may explain why therapy with Treatment Introduction a combination of cisplatin and by p53of p53 by Mutant p53 Normal p53 Mutant p53 paclitaxel has been successful independent gene therapy pathway in controlling some tumours that have not responded to Apoptosis Apoptosis Apoptosis cisplatin alone. 744
Vol 349 • March 15, 1997
COMMENTARY without resorting to physical ablation of prion-carrying cells (as in the case of SCID mice)? The normal prion protein, PrPC, may offer an intriguing handle. PrPC is crucial for prion spread within the CNS,9 and it is not unlikely to be required also for spread of prions from peripheral sites to CNS. If the latter suspicion is confirmed, a true opportunity may arise for interference with prion spread and, therefore, for secondary prevention of encephalopathy after exposure to prions. Given the availability of transgenic and knockout mice10,11 for PrPC, answers to these questions should not be far away.
Adriano Aguzzi Department of Pathology, University Hospital, Z urich CH-8091, Switzerland 1
Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science 1982; 216: 136–44. 2 Lasmezas CI, Deslys JP, Robain O, et al. Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science 1997; 275: 402–05. 3 Hill AF, Zeidler M, Ironside J, Collinge J. Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy. Lancet 1997; 349: 99. 4 Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF. Molecular analysis of prion strain variation and the aetiology of “new variant” CJD. Nature 1996; 383: 685–88. 5 Eklund CM, Kennedy RC, Hadlow WJ. Pathogenesis of scrapie virus infection in the mouse. J Infect Dis 1967; 117: 15–22. 6 Muramoto T, Kitamoto T, Hoque MZ, Tateishi J, Goto I. Species barrier prevents an abnormal isoform of prion protein from accumulating in follicular dendritic cells of mice with CreutzfeldtJakob disease. J Virol 1993; 67: 6808–10. 7 Lasmezas CI, Cesbron JY, Deslys JP, et al. Immune system-dependent and independent replication of the scrapie agent. J Virol 1996; 70: 1292–95. 8 Kimberlin RH, Walker CA. Pathogenesis of mouse scrapie: evidence for neural spread of infection to the CNS. J Gen Virol 1980; 51: 183–87. 9 Brandner S, Raeber A, Sailer A, et al. Normal host prion protein (PrPC) required for scrapie spread within the central nervous systme. Proc Natl Acad Sci USA 1996; 93: 13148–51. 10 Bueler H, Aguzzi A, Sailer A, et al. Mice devoid of PrP are resistant to scrapie. Cell 1003; 73: 1339-47. 11 Fischer M, Rulicke T, Raever A, et al. Prion protein (PrP) with aminoproximal deletions restoring susceptibility of PrP knockout mice to scrapie. Embo J 1996: 15: 1255-64.
Assault against respiratory syncytial virus: beginning of an era On the heels of the extraordinary success of effective immunisation against Haemophilus influenzae B, the race for prevention has moved on to another virulent pathogen, respiratory syncytial virus (RSV). Early attempts to conquer RSV with a formalin-inactivated vaccine brought disaster in the form of enhanced infection on exposure to wild virus. Now, more than 25 years later, the first effective prophylactic strategy against RSV has arrived: passive immunisation with a high-titre intravenous immune globulin product, RSV-IGIV. The PREVENT study1 has confirmed the initial report of efficacy of monthly RSV-IGIV infusions during the RSV season,2 prompting approval of RSV-IGIV by the US Food and Drug Administration.3 Most impressive about this well-designed, randomised, double-blind, placebocontrolled trial is its magnitude—54 study centres and 510 patients with clinically significant bronchopulmonary dysplasia and/or extreme prematurity recruited within a 5week period. Evidence of efficacy included significant decreases in hospital admissions and hospital days for RSV infections, in lengthy hospital stays for RSV, and in
Vol 349 • March 15, 1997
admissions for even non-RSV-associated respiratory illnesses. Although it made no impact on intensive-care unit stays, mechanical ventilation requirement, or mortality, prophylactic RSV-IGIV clearly reduced the severity of RSV lower-respiratory-tract infections in highrisk infants, outperforming past trials of ordinary immune globulin.4 Balanced against efficacy are issues of safety, practicality, and cost. A small percentage of treated infants experience adverse events, including respiratory distress, fluid overload, increased diuretic requirement, and difficulties with intravenous access.1,2,4 In addition, in all three randomised trials of RSV-IGIV, there were more deaths in the RSV-IGIV groups than in the control groups.1,2,5 Although not statistically significant, this observation is unexplained and cannot yet be discounted. Nor can the ever-present concern for transmission of unknown infectious agents be summarily dismissed. As for practicality, the regimen for RSV-IGIV is difficult. Even in the controlled setting of a clinical trial, only 82% of participants received >75% of each RSV-IGIV dose.1 The large number of at-risk patients presents both a logistic challenge and the burden of high cost. The one published cost-effectiveness analysis concluded that RSV-IGIV will increase medical costs, but that these expenditures are in line with other commonly used, albeit costly, medical interventions.6 The analysis includes the assumption that RSV-IGIV will save lives, a point that remains to be proven. So, as with any new prophylactic or therapeutic modality, we are left to decide how to incorporate RSVIGIV into our clinical practice. Because of issues of safety, practicality, and cost, it would be prudent to restrict prophylaxis to those at greatest risk.7 For infants with bronchopulmonary dysplasia, severity of RSV infection is most pronounced in children aged <2 years who have required supplementary oxygen in the preceding 6 months, which is also the group of patients with bronchopulmonary dysplasia in whom efficacy of RSVIGIV was shown in the PREVENT trial. For premature infants without lung disease, risk is greatest for those born before <32 weeks’ gestation (before passive transfer of maternal antibody), particularly those ≤6 months of chronological age (and especially those ≤3 months old, for whom efficacy in the PREVENT trial was maximum). A third group at risk from RSV, and for whom use of RSVIGIV would be tempting, are infants with congenital heart disease. However, in the initial RSV-IGIV trial, this subgroup benefited least from RSV-IGIV, and the immune globulin was associated with increased mortality.2 In a subsequent study of infants with congenital heart disease, no overall benefit of RSV-IGIV was observed, and in infants with cyanotic congenital heart disease, RSVIGIV was associated with increased surgical complications and mortality.5 Therefore, because both efficacy and safety are unresolved issues, RSV-IGIV cannot be recommended for children with congenital heart disease. Another group at risk of severe RSV disease are immune deficient patients, particularly those with congenital immune deficiencies and patients receiving chemotherapy or organ transplants. Studies of RSV-IGIV are needed in these patients; until they are done, RSV-IGIV prophylaxis would seem a reasonable empirical intervention during community or nosocomial outbreaks directly threatening 743
THE LANCET
COMMENTARY severely immunocompromised populations. In addition, although in two studies (one in low-risk infants and one in infants who were premature or had bronchopulmonary dysplasia or congenital heart disease) RSV-IGIV was not effective in the treatment of established RSV infections,7 uncontrolled experience at one institution suggested that the combination of high-titre intravenous immune globulin and aerosolised ribavirin might be of therapeutic value in immunocompromised patients.8 The hope is that prophylactic measures against RSV will become simpler and less expensive, thus more broadly applicable—perhaps with monoclonal antibodies and, eventually, active immunisation. RSV-IGIV is a promising first victory; it will probably be only the beginning of the end for RSV.
Such resistance has led many research groups to focus on the molecular pathways of drug resistance, with the aim of developing therapies to defined molecular targets.1 The involvement of the tumour-suppressor gene p53 in DNA repair and apoptosis has led to the suggestion that defects in p53 may determine resistance to chemotherapy.2 Mutations in p53 are the commonest gene mutations observed in human cancer, occurring in approximately 50% of mainly late-stage ovarian tumours.3 Most studies suggest that the presence of a p53 mutation confers a prognostic effect, increasing the aggressiveness of tumours, shortening progression-free intervals, and reducing overall survival rates.4 Many anticancer agents act by inducing apoptosis. Platinum-based drugs (for example, cisplatin) cause DNA damage in dividing cells. When faced with such Mark J Abzug DNA damage, normal cells increase p53 expression and Pediatric Infectious Diseases, University of Colorado School of Medicine respond by either of two pathways. p53 can act to protect and the Children’s Hospital, Denver, Colorado 80218, USA the cell, by halting the cell cycle, thereby allowing the 1 Connor E, Top F, Kramer A, and the PREVENT Study Group. cell to repair the damage. Alternatively, if the damage is Reduction of respiratory syncytial virus hospitalization among too great, the other pathway is initiated, destroying the premature infants and infants with bronchopulmonary dysplasia using damaged cell by apoptosis. The predominant pathway respiratory syncytial virus immune globulin prophylaxis. Pediatrics 1997; 99: 93–99. will depend on the cell type, cellular and molecular 2 Groothuis JR, Simoes EAF, Levin MJ, et al. Prophylactic environment, and degree of DNA damage. Clearly, administration of respiratory syncytial virus immune globulin to highdevising ways to activate only the apoptotic pathway risk infants and young children. N Engl J Med 1993; 329: 1524–30. should lead to better treatment outcome. 3 Nightingale SL. First product available for preventing serious RSV disease. JAMA 1996; 275: 902. What occurs when p53 is absent or is mutated? The 4 Groothuis JR, Simoes EAF, Hemming VG, and the Respiratory tumour cell is unable to undergo p53-mediated cell-cycle Syncytial Virus Immune Globulin Study Group. Respiratory syncytial arrest or apoptosis, which leads to the continued growth virus (RSV) infection in preterm infants and the protective effects of RSV Immune Globulin. Pediatrics 1995; 95: 463–67. of aberrant cells. Laboratory tests on cancer cell-lines in 5 Simoes EAF, Sondheimer HM, Meissner HC, Welliver RC, Groothuis vitro show that mutations in p53 lead to suppression of JR, and the RSVIG Cardiac Study Group. Respiratory syncytial virus the apoptotic pathway, and to chemoresistance. In immunoglobulin as prophylaxis against respiratory syncytial virus in addition, replacing normal p53 function, or stimulating children with congenital heart disease. Pediatr Res 1996; 39: 113A (abstract 662). the apoptotic pathway, leads to the re-establishment of 6 Hay JW, Ernst RL, Meissner HC. Respiratory syncytial virus immune chemosensitivity. In general, tumours with normal p53 globulin: a cost-effectiveness analysis. Am J Man Care 1996; 2: are considered more chemosensitive, whereas tumours 851–61. with mutant p53 are more chemoresistant.5.6 This reflects 7 Meissner HC, Welliver RC, Chartrand SA, Fulton DR, Rodriguez WJA, Groothuis JR. Prevention of respiratory syncytial virus the capability of a particular cell to respond to the DNA infection in high risk infants: consensus opinion on the role of damage by undergoing apoptosis. immunoprophylaxis with respiratory syncytial virus hyperimmune Where does that leave us with expectations for the globulin. Pediatr Infect Dis J 1996; 15: 1059–68. 8 Whimbey E, Champlin RE, Englund JA, et al. Combination therapy future, and will molecular analysis of p53 lead to with aerosolized ribavirin and intravenous immunoglobulin for improved treatment of ovarian cancer? Clearly, the respiratory syncytial virus disease in adult bone marrow transplant determination of p53 mutation status is important in recipients. Bone Marrow Transplant 1995; 16: 393–99. devising the treatment strategy for the ovarian cancer patient, since tumours with p53 mutations would seem to have a worse prognosis and increased Role of p53 in drug resistance in ovarian chemoresistance, requiring aggressive or experimental cancer treatment. The determination of “apoptotic competence” of the tumour cells may be even more The basis of drug resistance in ovarian cancer has been helpful than p53 mutation status as a predictor of the subject of intensive scientific and clinical treatment outcome. In tumours with p53 mutations, investigations over several years. Whilst most ovarian replacement of normal p53 gene by gene therapy, or cancer patients will initially respond to non-specific treatment with apoptosis-regulating molecules may be chemotherapy, such as cisplatin, only a minority will be successful strategies. In addition, the use of drug cured, because of innate or acquired drug resistance. treatments that do not require Exploiting p53 in drug response by ovarian cancer p53-dependent apoptosis, such as paclitaxel, may help Chemosensitive tumour Chemoresistant tumour Potential therapy overcome resistance,7 and Chemotherapy Chemotherapy Chemotherapy may explain why therapy with Treatment Introduction a combination of cisplatin and by p53of p53 by Mutant p53 Normal p53 Mutant p53 paclitaxel has been successful independent gene therapy pathway in controlling some tumours that have not responded to Apoptosis Apoptosis Apoptosis cisplatin alone. 744
Vol 349 • March 15, 1997