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Anticancer drugs
Anticancer drugs can be used against many targets within cancer cells. Lower doses can cause apoptosis, mediated by p53, while higher doses can cause necrosis.
Cytotoxic effects to healthy tissues are reduced because pf healthy tissue rebound
Some drugs are cell cycle-specific and work best for quickly growing cancers; others are cycle non-specific (ie cyclophosphamide or doxorubicin) and are needed for slow growing cancers.
Multi-drug resistance can be a big problem, especially against drugs derived from natural products (ie doxorubicin, vincristine, etoposide)
- DNA wreckers
- DNA synthesis (antimetabolites)
- microtubule inhibitors
- hormonal agents
- molecular targeted agents
DNA Wreckers
Alkylating agents
- cross-link DNA, binding convalently to N7 on guanine bases
- work at any phase of the cell cycle
- also bind lipids, proteins, -SH, -OH, -NH groups
- cisplatin is not alkylating, but does cross-link DNA
- cyclophosphamide: must be metabolized first by CYP450
- very toxic; severe side effects, and can cause 2e cancers
- cyclophosphamide especially linked to alopecia and hemorragic cystitis
Intercalating agents (anthracyclines)
- interfere with the helix and the proteins that interact with it
- block DNA/RNA synthesis
- work throughout cell cycle
- induce DNA breakage, inhibit topo II
- release free radicals
- wide spectrum of use
- doxorubicin
- dose-dependent, cumulative , and potentially fatal cardiotoxicity due to free radical release
Topoisomerase Inhibitors
- interfere with the machinery involved with strand breaks
- work during S phase but especially G2
Topoisomerase I inhibitors
- camptothecins
- irinotecan (prodrug, activated in liver)
Topoisomerase II inhibitors
- etoposide (VP-16)
- act in late S and G2 phase
Antimetabolites
Antimetabolites interfere with DNA synthesis; work best during S phase
Purine antagonists
- 6-mercaptopurine, used primarily for childhood leukemias
- prodrug nucleotide
- metabolism can be interefered with by anti-gout medication
Pyrimidine antagonists
- 5-fluorouracil
- prodrug
- inhibits thymidine synthetase
Cofactor antagonists
- folic acid is required for both purine and pyrimidine synthesis
- methotrexate
- taken into cell by folate uptake carrier
- inhibits dihydrofolate reductase (DHFR)
- resistance can develop due to increased or mutated DHFR, or decreased folate carrier protein
Microtubule Inhibitors
- work best during M phase
vinca alkaloids
- destabilize MTs
- vincristine
- from periwinkle plant
- used to treat childhood leukemias
taxanes
- increase MT stability
- paciltaxel (Taxol)
Hormonal Agents
- leuprolide is an GnRH analogue; initially increased LH/FSH production, then decreases it
- letrozole inhibits aromatoase, preventing estrogen production
- tamoxifen antagonizes the estrogen receptor
- also works on melanoma
Molecular Targeted Agents
Combination Therapy
Combination therapy reduces multidrug resistance, combines different mechanisms, and reduces side effects associated with specific drugs.