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WHAT ARE THE MAJOR DRAWBACKS OF CONVENTIONAL CHEMOTHERAPEUTIC AGENTS?

WHAT ARE THE MAJOR DRAWBACKS OF CONVENTIONAL CHEMOTHERAPEUTIC AGENTS?. 1. 2. 1. POOR SELECTIVITY. LOW THERAPEUTIC INDEX. 2. DRUG RESISTANCE. TARGETED AGENTS IN ANTICANCER CHEMOTHERAPY. ONCOGENE ACTIVATION. ONCOGENE ACTIVATION. TUMOR SUPPRESSOR INACTIVATION. 1) Point mutation. p53.

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WHAT ARE THE MAJOR DRAWBACKS OF CONVENTIONAL CHEMOTHERAPEUTIC AGENTS?

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  1. WHAT ARE THE MAJOR DRAWBACKS OF CONVENTIONAL CHEMOTHERAPEUTIC AGENTS? 1 2

  2. 1 POOR SELECTIVITY LOW THERAPEUTIC INDEX

  3. 2 DRUG RESISTANCE

  4. TARGETED AGENTS IN ANTICANCER CHEMOTHERAPY

  5. ONCOGENE ACTIVATION

  6. ONCOGENE ACTIVATION

  7. TUMOR SUPPRESSOR INACTIVATION 1) Point mutation p53

  8. TUMOR SUPPRESSOR INACTIVATION 1) Point mutation: p53, BRCA1 etc. 2) Deletion 3) Epigeneticsilencing

  9. Locus 9p21

  10. TUMOR SUPPRESSOR INACTIVATION 1) Point mutation: p53, BRCA1 etc. 2) Deletion 3) Epigeneticsilencing 4) Protein-proteininteractions

  11. TUMOR SUPPRESSOR INACTIVATION Protein-protein interactions

  12. Table 1 Examples of oncogene addiction: studies in mice Weinstein IB and Joe AK (2006) Mechanisms of Disease: oncogene addiction—a rationale for molecular targeting in cancer therapy Nat Clin Pract Oncol 3: 448–457 10.1038/ncponc0558

  13. Table 2 Examples of oncogene addiction: studies in human cancer cell lines Weinstein IB and Joe AK (2006) Mechanisms of Disease: oncogene addiction—a rationale for molecular targeting in cancer therapy Nat Clin Pract Oncol 3: 448–457 10.1038/ncponc0558

  14. Table 3 Clinical evidence of oncogene addiction Weinstein IB and Joe AK (2006) Mechanisms of Disease: oncogene addiction—a rationale for molecular targeting in cancer therapy Nat Clin Pract Oncol 3: 448–457 10.1038/ncponc0558

  15. MODELS OF ONCOGENE ADDICTION

  16. MODELS OF ONCOGENE ADDICTION

  17. MODELS OF ONCOGENE ADDICTION

  18. Twogenes (‘A’ and ‘B’) are said to be synthetic lethal if mutation of either gene alone is compatible with viability but simultaneous mutation of both genes causes death.

  19. % B inhibition % B inhibition

  20. Cellula normale PTEN Cellula tumorale PTEN effetti lievi attività PI3K/Akt/mTOR INIBITORI DI mTOR attività PI3K/Akt/mTOR

  21. Cellula normale BRCA1 BRCA1 Cellula tumorale BER SSB riparazione DSB HR BER SSB riparazione DSB Instabilità genomica HR

  22. Cellula normale BRCA1 BRCA1 Cellula tumorale INIBITORI DI PARP BER DSB riparazione SSB HR DSB riparazione HR INIBITORI DI PARP BER HR SSB DSB DSB HR

  23. Cellula normale Rb Rb Cellula tumorale SOPRAVVIVENZA blocco attività E2F VELENI DELLA TOPO II  espressione gene A  espressione gene topoisomerasi II  attività E2F  espressione gene B  espressione gene C

  24. HOW CAN WE SELECTIVELY TARGET TUMOR RELEVANT DEFECTS? INHIBIT GENE EXPRESSION INHIBIT PROTEIN FUNCTION Small molecule inhibitors AS-ODN mAbs siRNA

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