Cancer therapy Flashcards
Anti-cancer drug classes
Anti-metabolites
Cytotoxic antibotics
Alklating drugs
Alkaloids and taxans
Anti-neoplastic drugs
Action of cell cycle specific drugs
Usually target a specific cell cycle phase. Most effective in rapidly proliferating cancer cells.
Drugs which are cell cycle non-specific kill tumour cells in cycling and resing phases of the cell cycle.
How does resistance to anti-cancer drugs develop?
Increased rate of DNA repair: e.g. when alkylating agents are used
Formation of trapping agents for ROS
Change in target enzymes
Reduced prodrug activation
Drug inactivation
Transporter
Adverse effects of cancer drugs
Tissue necrosis
Targets rapidly dividing normal cells: skin, gut, marrow, germ cells
Death of large numbers of cancer cells causes hyperuricaemia, renal failure
Immunosuppression, leads to infection or secondary tumours
Drug specific effects e.g. renal toxicity.
Role of drug combinations
Provides a maximal cell kill within a range of toxicity tolerated by the host.
Provides a broader range of interaction between drugs and tumour cells with different genetic abnormalities in a heterogenous tumour population.
Helps prevent against development of resistance.
Alkylating agents
Exert their effects by transferring alkyl groups to DNA (and other parts of the cell). This causes cross-linking of the DNA which leads to mis-pairing and subsequent DNA breaks in the DNA backbone.
Replicating cells are most susceptible to these drugs.
Cells may become resistant by increasing their capacity to repair DNA lesions, reduce transport of the drug into the cell or by conjugating the drug which reduces its activity.
Adverse effects are dose-related. Primarily occurs in rapidly dividing tissues. Increased risk of secondary malignancies.
Anti-metabolites
Utilises differences in metabolism between cancer cells and normal cells. They mimic endogenous compounds and have anti-cancer and immunosuppressant effects.
Antagonise folate, purine and pyrimidines
Antifolates
Folic acid antagonists. e.g. methotrexate
MTX is a folate analog that binds to dihydrofolate reductase. This enzyme converst dihydrofolate to tetrahydrofolate, which is required for purine and amino acid synthesis (Met, Ser). Inhibition prevents formation of DNA, RNA and cellular proteins.
Action of MTX is increased by polyglutamates which are selectively retained in cancer cells. Drug is excreted renally. Therefore needs to be monitored carefully in renal impairment.
Used in acute leukemia, lymphomas, psoriasis, Rh disease.
Folinic acid (form FH4) reduces side effects of MTX
Purine analogues
Purine analogues e.g. AZT, mercaptopurine, thioguanine reduce DNA and RNA synthesis. However, they have low efficacy as a single treatment.
Drugs are metabolised by HGPRT (hypoxanthine-guanine phosphoribosyl transferase) to form toxic nucleotides which inhibits several enzymes involved in purine synthesis.
Used in acute leuekemias and CML.
Adverse effects: liver necrosis and cholestasis.
Factors that affect response to cancer treatment
Cell type
Early diagnosis
AIDS/Immunosuppression
Genetics
Main mechanisms of anti-cancer drugs
Prevents DNA synthesis (low toxicity for patient)
Inhibits replication of preformed DNA e.g. cytotoxic antibodies/ alkylating agents (more toxic)
Prevent microtubule formation (stops the cell dividing)
Two examples of pyrimidine analogues
Cytarabine: similar to cytidine.
5-Fluorouracil:
Converted by enzymes into nucleotide metabolites. FdUMP forms a covalent complex with theymidylate synthase which results in inhibition of DNA synthesis. 5-FU is also converted into FUTP/FdUTP which is incorporated into RNA and DNA respectively.
Drug used for colorectal, breast, bladder and liver cancers.
Action of cytotoxic antibiotics
Intercalates DNA bases which blocks transcrption.
Stimulates topoisomerase II induced dsDNA breaks
Causes free radical production which damages DNA
Binds to cell membranes to alter fluidity and transport
Examples of 3 cytotoxic antiboiotics
Doxorubicin and daunorubicin: Metabolised to free radicals, cause DNA breaks by stimulating topoII. Maximum effect in S-phase. Both are cardio-toxic. Doxyrubicin active for lymphomas and solid tumours. Daunorubicin active for lymphomas and leukemias.
Bleomycin: Binds to DNA and generates free radicals which cause ss and ds breaks. This stops DNA synthesis. Arrests cells in G2 of the cell cycle. Used for treatment of HL and NHL. Causes pigementation of the skin and pulmonary fibrosis.
Etoposide: Stimulates topoII which causes DNA breaks. Clinical activity against germ cell tumours. HL and NHL and Kaposi’s sarcoma. Targets rapidly diving cells.
Examples of alkylating agents
Cyclophosphamide: Oral drug activated by P450 enzymes in the liver. Alkylate nucleotide bases of DNA causing cells to arrest in G2 as DNA cannot divivde. Has maximum effect in S phase. Used in combination against lymphoma, leukemia, choriocarcinoma. Causes harmorrhagic cystitis because by-product of metabolism acrolein has bladder toxicity.
Platinum analogues (cisplatin, carbiplatin): Kill cells at all stages of the cell cycle (most effective S phase). Forms links between DNA strands. Used against solid tumours. Cleared by the kidneys - nephrotoxic, causes peripheral neurophathy.
