Antimicrobial and anticancer drugs
Diperkenalkan| English | Makna |
|---|---|
| selective toxicity | selective toxicity |
| cell-cycle-specific | cell-cycle-specific |
Killing the invader, sparing the host
- Penicillin can kill bacteria at doses that barely touch human cells. Cancer drugs, in contrast, make hair fall out and blood counts drop.
- Both fields rely on selective toxicity 选择性毒性. What makes the difference is what the target cell has that ours lack.
Antibacterial targets
- β-lactams block cell-wall building; human cells have no wall. Other drugs hit the bacterial ribosome (30S and 50S, not our 80S) or DNA gyrase.
- Sulfonamides and trimethoprim block bacterial folate synthesis; we take folate in from food.
Match each drug group to its bacterial target.
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Each target is missing or different in human cells.
β-lactams are selective because human cells have no cell wall.
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The target does not exist in our cells.
Resistance is arithmetic
- Resistance mutations arise at about 10⁻⁷ to 10⁻⁹ per cell. A large infection already holds some resistant cells before treatment starts.
- One drug selects them. Two drugs with different targets need two mutations in one cell, so combinations last longer (as in tuberculosis).
(Illustrative) 10¹¹ bacteria, resistance mutation rate 10⁻⁹ per cell. How many resistant cells are expected before treatment?
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10¹¹ × 10⁻⁹ = 10² = 100.
Anticancer: hitting the cycle
- Cell-cycle-specific 细胞周期特异性 drugs hit dividing cells: antimetabolites (methotrexate, fluorouracil) in S phase; vinca alkaloids and taxanes in M phase.
- Alkylating agents damage DNA in any phase of the cycle.
Match each anticancer drug group to when it acts.
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Cycle specificity shapes the schedule.
Why cancer drugs have narrow margins
- Cancer selectivity depends on timing, not on a missing structure. Marrow, gut lining and hair follicles also divide quickly.
- So the expected toxicities are low blood counts, mouth ulcers and diarrhoea, and hair loss.
Which tissue is least likely to be harmed by cell-cycle-specific chemotherapy?
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Adult neurons rarely divide; the other three divide quickly.
Schedule follows the cycle
- An S-phase drug given as one short burst misses cells not in S phase at that moment. Spread over time, it meets more of them.
- Each cycle kills a fixed fraction of cells, not a fixed number, so repeated cycles are needed.
Worked example: one drug or two?
- (Illustrative) An infection holds 10¹⁰ bacteria; resistance to drug A arises at 10⁻⁸ per cell: 10¹⁰ × 10⁻⁸ = 100 resistant cells already present.
- Resistance to both A and B needs both: 10⁻⁸ × 10⁻⁸ = 10⁻¹⁶ per cell, so 10¹⁰ × 10⁻¹⁶ = 10⁻⁶. Almost certainly none.
Put the steps of resistance emerging in order.
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The drug selects resistance; it does not create it.
Worked example: fractional kill
- (Illustrative) A tumour holds 10⁹ cells and each cycle kills 99%, leaving 1 in 100.
- After 1 cycle: 10⁷. After 3 cycles: 10⁹ × 10⁻⁶ = 10³ cells, still present though too few to see.
(Illustrative) A tumour holds 10¹⁰ cells and each cycle kills 90%. How many cells remain after 4 cycles?
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Each cycle leaves 1 in 10, so 10¹⁰ × 10⁻⁴ = 10⁶.
Three common slips
- Expecting cancer drugs to spare normal dividing tissue. Marrow and gut lining divide too.
- Calling antimetabolites non-specific. They are S-phase specific.
- Blaming resistance on the drug weakening. The drug selects mutants that were already there.
Recap
- Antibacterial targets ours lack: wall, 70S ribosome, gyrase, folate synthesis.
- Resistance: mutation supply × selection; two targets multiply the odds against it.
- Anticancer: S phase (antimetabolites), M phase (vincas, taxanes), any phase (alkylators); toxicity in marrow, gut and hair; fixed fractional kill per cycle.