Screening of Anticancer Drugs

Screening of Anticancer Drugs

1. Definition, rationale & overview

• Screening of anticancer drugs is the systematic, tiered preclinical testing of candidate compounds for antitumour / antiproliferative activity, using in-vitro (cell-based) and in-vivo (animal) models, to identify and prioritise molecules of potential therapeutic value before clinical trials (SK Gupta 3e Ch.10, pp.170–187).
• Driving need: cancer is, on a worldwide basis, the single largest cause of death in both men and women; >100 distinct cancer types exist; it is a multifactorial disease whose biology is incompletely understood — pathogenesis implicates induction of proto-oncogenes + inhibition of tumour-suppressor genes and angiogenesis (VEGF, esp. VEGF-A; PTTG1 over-expression; FOXO1 down-regulation) (SK Gupta 3e Ch.10, pp.170–171).
• Currently used cytotoxic chemotherapeutics suffer high toxicity (bone-marrow suppression, alopecia, nausea/vomiting) and poor affordability — this drives the search for quick, novel screening methods capable of triaging large compound libraries (SK Gupta 3e Ch.10, p.171).
• Anticancer drugs are sourced from natural products (plants, microbes) and synthetic molecules; oncology is the third-largest therapeutic market after CNS and cardiovascular drugs (number of "blockbuster" anticancer drugs with ≥$1 billion sales rose from 19 in 2007 to 24 in 2008) (SK Gupta 3e Ch.10, pp.170–171).
• Tiered screening cascade (general logic): large compound libraries → primary in-vitro cytotoxicity screen (rapid, cheap, high-throughput) → secondary in-vivo confirmation (host-mediated activity, therapeutic ratio) → most promising candidate tested in >1 animal model → clinical development (SK Gupta 3e Ch.10, pp.171, 176–177).
• Treatment failure in advanced cancer arises from improper diagnosis/treatment or from development of resistance to anticancer agents; resistant tumours are deliberately built into screening panels to flag agents active against resistant disease (SK Gupta 3e Ch.10, pp.170, 176–177).

In-vitro vs in-vivo — the strategic trade-off

• In-vitro models are run first (before in-vivo) because they are: (1) less time-consuming; (2) more cost-effective; (3) allow small quantities + large numbers of compounds to be tested; (4) easier to manage; and can be cultured under a controlled environment (pH, temperature, humidity, O₂/CO₂ balance) giving homogeneous cell batches and minimising experimental error (SK Gupta 3e Ch.10, p.171).
• In-vitro disadvantages: (1) false positives (active in-vitro, inactive in-vivo); (2) false negatives (inactive in-vitro but active in-vivo — needs in-vivo biotransformation to the active metabolite); (3) pharmacokinetics cannot be evaluated in-vitro; (4) the geometry of solid tumours in-vivo differs greatly from cells growing in suspension/monolayer (SK Gupta 3e Ch.10, p.171).
• In-vivo advantages: detect host-mediated activity, relatively predictable, estimate the therapeutic ratio, and detect agents irrespective of mechanism of action; high-efficacy/broad-spectrum activity in animals usually predicts clinical efficacy (with exceptions due to metabolic differences + cancer-cell heterogeneity between rodents and humans) (SK Gupta 3e Ch.10, p.177).
• In-vivo disadvantages: lower sensitivity, costly, time-consuming, few samples handleable, difficult to manage (SK Gupta 3e Ch.10, p.177).