Sceptical scientists
2001; Elsevier BV; Volume: 358; Linguagem: Inglês
10.1016/s0140-6736(01)07024-6
ISSN1474-547X
Autores Tópico(s)Fungal Plant Pathogen Control
ResumoBrian J Druker isprofessor of medicine, Division of Hematology and Medical Oncology, and Director of Leukemia Center in the OHSU Cancer Institute at Oregon Health and Science University in Portland.The approval of STI571 (Novartis Pharma AG, Basel, Switzerland), an agent targeted against the causative molecular event in chronic myeloid leukaemia, has been heralded as a major advance in the treatment of cancer. The history of chronic myeloid leukaemia is notable for many firsts, but as with many firsts, they were often met with great scepticism. In 1960, when Nowell and Hungerford described a shortened chromosome in the bone marrows of patients with chronic myeloid leukaemia as the first consistent chromosomal abnormality associated with a human cancer, most thought that their discovery was an associated event, and few considered it a causative one. Janet Rowley met with similar scepticism in 1973, when she reported that this abnormal chromosome, now called the Philadelphia chromosome, came about as a reciprocal translocation between chromosomes 9 and 22, another first. Even after scientists had shown that this balanced translocation resulted in the production of the constitutively activated tyrosine kinase, Bcr-Abl, there remained scepticism about the fact that Bcr-Abl was the causative molecular abnormality in the disease. Rather, people thought that Bcr-Abl might be a secondary event or an associated molecular abnormality, despite the fact that tyrosine kinases regulate cellular growth and several oncogenic retroviruses, including the highly related v-Abl, induced tumours in animals.In 1990, however, G Daley, O Witte, and J Groffen published reports, which showed Bcr-Abl, as a sole oncogenic event, induced leukaemia in animals. Thus, Bcr-Abl, present in 95% of patients with chronic myeloid leukaemia, was firmly established as the causative molecular abnormality of the disease. A specific inhibitor of the Bcr-Abl tyrosine kinase would, therefore, be expected to be an effective and selective therapeutic agent for leukaemia.Tyrosine kinases are key components of signal transduction pathways, which regulate cell growth, differentiation, and survival. They function by catalysing the transfer of phosphate from ATP to tyrosine residues on substrate proteins, leading to alterations in substrate structure and function (figure). Since all protein kinases use ATP as a phosphate donor, and because there is a high degree of conservation among kinase domains, particularly in the ATP binding sites, many people thought that inhibitors of ATP binding would lack sufficient specificity to be clinically useful. Despite this scepticism, by the late 1980s, several relatively specific compounds had been developed in academic laboratories and by the pharmaceutical industry. We tested one such compound, STI571, which inhibits the Bcr-Abl tyrosine kinase, the platelet derived growth factor receptor, and the receptor for stem-cell factor, c-kit, but no other tyrosine kinases. Because of its in-vitro selectivity against chronic myeloid leukaemia cells and pharmacokinetic and fomulation properties, STI571 emerged as the lead compound for clinical development. The compound has significant clinical benefits when given to patients with any phase of chronic myeloid leukaemia, and has few side-effects. In chronic-phase patients, who have failed standard therapy with interferon, over 90% regain normal blood counts, typically in 4–6 weeks of starting treatment. The bone marrows of over 30% of these patients are negative for the Philadelphia chromosome by routine cytogenetic assessment. However, more sensitive techniques, such as PCR, can still detect Bcr-Abl transcripts in most patients. The blast phase of the disease, which is highly refractory to treatment, including high-dose chemotherapy, has nearly a 60% response rate to single agent STI571, but most individuals relapse while on therapy. The mechanisms of relapse are being investigated. Results of one study have shown that some patients who relapse develop Bcr-Abl point mutations that render the Bcr-Abl kinase insensitive to inhibition by STI571.FigureBcr-Abl tyrosine kinase Bcr-Abl tyrosine kinase is a constitutively active kinase that binds ATP and transfers phosphate from ATP to tyrosine (TYR) residues on various substrates. This activity causes the excess proliferation of myeloid cells characteristic of chronic myeloid leukaemia (CML). STI571 blocks the binding of ATP to Bcr-Abl tyrosine kinase, inhibiting the activity of the kinase. In the absence of tyrosine kinase activity, substrates required for Bcr-Abl function cannot be phosphorylated.View Large Image Figure ViewerDownload Hi-res image Download (PPT)STI571 is also highly effective in a rare intestinal tumour known as gastrointestinal stromal tumour. This tumour, driven by mutations in the c-kit gene that produce a hyperactive c-kit tyrosine kinase, is also highly refractory to chemotherapy, with response rates of less than 5%. Objective responses to STI571 have been seen in over 60% of patients. In both the intestinal tumour and leukaemia examples, the main reason for the effectiveness of STI571 is that the drug targets an important pathogenetic event in the malignant disease. Although c-kit and the platelet derived growth factor receptor are expressed in many cancers, in most, the data that support a pathogenetic role for these proteins are limited. However, the notion that a precise understanding of the pathogenesis of a cancer can lead to more effective and less toxic therapies has been validated in the clinical trials of STI571. To recapitulate the success of STI571 in other malignant diseases, the first task is to identify the pathogenetic events in every cancer. Brian J Druker isprofessor of medicine, Division of Hematology and Medical Oncology, and Director of Leukemia Center in the OHSU Cancer Institute at Oregon Health and Science University in Portland. The approval of STI571 (Novartis Pharma AG, Basel, Switzerland), an agent targeted against the causative molecular event in chronic myeloid leukaemia, has been heralded as a major advance in the treatment of cancer. The history of chronic myeloid leukaemia is notable for many firsts, but as with many firsts, they were often met with great scepticism. In 1960, when Nowell and Hungerford described a shortened chromosome in the bone marrows of patients with chronic myeloid leukaemia as the first consistent chromosomal abnormality associated with a human cancer, most thought that their discovery was an associated event, and few considered it a causative one. Janet Rowley met with similar scepticism in 1973, when she reported that this abnormal chromosome, now called the Philadelphia chromosome, came about as a reciprocal translocation between chromosomes 9 and 22, another first. Even after scientists had shown that this balanced translocation resulted in the production of the constitutively activated tyrosine kinase, Bcr-Abl, there remained scepticism about the fact that Bcr-Abl was the causative molecular abnormality in the disease. Rather, people thought that Bcr-Abl might be a secondary event or an associated molecular abnormality, despite the fact that tyrosine kinases regulate cellular growth and several oncogenic retroviruses, including the highly related v-Abl, induced tumours in animals. In 1990, however, G Daley, O Witte, and J Groffen published reports, which showed Bcr-Abl, as a sole oncogenic event, induced leukaemia in animals. Thus, Bcr-Abl, present in 95% of patients with chronic myeloid leukaemia, was firmly established as the causative molecular abnormality of the disease. A specific inhibitor of the Bcr-Abl tyrosine kinase would, therefore, be expected to be an effective and selective therapeutic agent for leukaemia. Tyrosine kinases are key components of signal transduction pathways, which regulate cell growth, differentiation, and survival. They function by catalysing the transfer of phosphate from ATP to tyrosine residues on substrate proteins, leading to alterations in substrate structure and function (figure). Since all protein kinases use ATP as a phosphate donor, and because there is a high degree of conservation among kinase domains, particularly in the ATP binding sites, many people thought that inhibitors of ATP binding would lack sufficient specificity to be clinically useful. Despite this scepticism, by the late 1980s, several relatively specific compounds had been developed in academic laboratories and by the pharmaceutical industry. We tested one such compound, STI571, which inhibits the Bcr-Abl tyrosine kinase, the platelet derived growth factor receptor, and the receptor for stem-cell factor, c-kit, but no other tyrosine kinases. Because of its in-vitro selectivity against chronic myeloid leukaemia cells and pharmacokinetic and fomulation properties, STI571 emerged as the lead compound for clinical development. The compound has significant clinical benefits when given to patients with any phase of chronic myeloid leukaemia, and has few side-effects. In chronic-phase patients, who have failed standard therapy with interferon, over 90% regain normal blood counts, typically in 4–6 weeks of starting treatment. The bone marrows of over 30% of these patients are negative for the Philadelphia chromosome by routine cytogenetic assessment. However, more sensitive techniques, such as PCR, can still detect Bcr-Abl transcripts in most patients. The blast phase of the disease, which is highly refractory to treatment, including high-dose chemotherapy, has nearly a 60% response rate to single agent STI571, but most individuals relapse while on therapy. The mechanisms of relapse are being investigated. Results of one study have shown that some patients who relapse develop Bcr-Abl point mutations that render the Bcr-Abl kinase insensitive to inhibition by STI571. STI571 is also highly effective in a rare intestinal tumour known as gastrointestinal stromal tumour. This tumour, driven by mutations in the c-kit gene that produce a hyperactive c-kit tyrosine kinase, is also highly refractory to chemotherapy, with response rates of less than 5%. Objective responses to STI571 have been seen in over 60% of patients. In both the intestinal tumour and leukaemia examples, the main reason for the effectiveness of STI571 is that the drug targets an important pathogenetic event in the malignant disease. Although c-kit and the platelet derived growth factor receptor are expressed in many cancers, in most, the data that support a pathogenetic role for these proteins are limited. However, the notion that a precise understanding of the pathogenesis of a cancer can lead to more effective and less toxic therapies has been validated in the clinical trials of STI571. To recapitulate the success of STI571 in other malignant diseases, the first task is to identify the pathogenetic events in every cancer.
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