Anticancer - cytotoxic drugs (chemotherapy)

Cytotoxic drugs (chemotherapy)

• If patients don’t have an obvious driving mutation must treat with cytotoxic drugs  

• Chemotherapies try to kill fast-growing cells 

• Drugs target different phases of the cell cycle – mainly DNA synthesis or replication or segregation (S phase) of genetic material (M phase) 

• However, cancer cells develop efflux mechanisms or increase the repair system to avoid this 

The cell cycle

• G1 – prepares cells for DNA synthesis  

  • Making proteins 

  • Cell grows larger  

• S phase – cell generates complete copy of genetic material  

  • 2 copies of DNA make in preparation for dividing  

• G2 phase – cell prepares for mitosis  

  • Cell continues to grow and make more proteins for the final stage  

• M phase – replicated DNA is condensed and segregated into chromosomes  

  • Cell splits and evenly distributes the DNA between the two cells 

• G0 phase – resting state (some cells establish mechanisms to stay in G0 phase until the drug is removed) 

• Throughout the cell cycle cells have checkpoints to ensure that mutated cells are not allowed to replicate 

Chemotherapy drugs

• Some can act on cells even during the resting phase whilst some can only act at specific cell cycle stages  

  • E.g: some bind to the DNA during replication preventing the DNA from being replicated  

  • E.g: some prevent the cells from splitting into daughter cells by preventing the DNA from being equally divided between the cells 

• Also damage healthy cells which divide rapidly à hair cells, GI mucosa cells, bone marrow cells etc. which are responsible for causing side effects.  

• Combination chemotherapy can be used to target different phases of the cell cycle 

Classes of chemotherapy

Generally, all classes of chemotherapy directly interact with the DNA or prevent the segregation of DNA  

• Alkylating agents: interact with DNA to stop DNA synthesis  

  • cross link DNA so it cent form 2 strands 

  • mainky affects S phase but also G1

• Taxanes: prevent segregation by targeting the microtuvules  

• Topoisomerase 2 inhibitors: interacts with DNA synthesis by preventing the unwinding of supercoiled DNA 

• Platinum complexes

  • cisplatin reduces DNA so it cant separate 

• Anthracyclins: also interact with DNA 

• Antimetabolites: prevent DNA synthesis 

• Tubulin interactive agents: prevent M phase occurring

Antimetabolites  

1. Methotrexate 

2. 5-FU  

3. Cytarabine 

1. Methotrexate 

• Methotrexate is an analogue of folic acid —> which inhibits dihydrofolate reductase and thereby inhibits one carbon transfers required for nucleic acid synthesis 

• Selective rescue of normal cells may be achieved with leucovorin (citrovorum factor)  

• Ways that the cancer can confer resistance:  

  • Decreased transport  

  • Decreased affinity of target enzyme  

  • Gene amplification and increased synthesis of target enzyme 

Antimetabolites  

1. Methotrexate  

2. 5-FU 

3. Cytarabine 

2. 5-FU (5 fluorouracil) 

• 5-FU analog of thymine (crucial nucleotide of DNA replication) 

• Metabolised into ribo and deoxyribonucleoside phosphates  

• Inhibition of thymidylate synthetase by 5-fluoro-2-deoxyuridide-5-monophosphate  

• In addition, theres incorporation of 5-fluorouridide triphosphate into RNA  

• Resistance cofered by:  

  • Increased synthesis of altered affinity target enzymes  

  • Decreased activation  

  • Increased catabolism  

• Works throughout the cell cycle, mainly S phase 

• Toxicity: myelosuppression, nausea, vomiting, anorexia, alopecia  

• Therapeutic use:  

  • GI tract adenocarcinomas 

  •  combination protocols for breast cancer 

  • Topical application for premalignant keratoses 

Antimetabolites  

1. Methotrexate  

2. 5-FU  

3. Cytarabine 

3. Cytarabine 

• Cytarabine is an analogue of pyrimidine nucleoside but with the substitution of arabinose for ribose 

• Chemical nature: 1-beta-arabinofuranosylcytosine  

• The triphosphate metabolite inhibits DNA polymerase  

• Resistance is conferred by:  

  • Decreased kinase activity required for activation  

  • Increased inactivation by deaminase  

• Cell cyle specific for the S phase and blocks progression from G1 to S phase  

• Causes nausea, vomiting, myleosupression  

• Excreted chiefly as the noncytotoxic metabolite uracil arabinoside  

• Deamination can be inhibited by tetrahydrouridine 

Plant alkaloids - mitotic inhibitors

1. Vinca alkaloids: vincristine, vinblastine and vinorelbine  

2. Taxanes: paclitaxel and docetaxel  

3. Podophyllotoxins: etoposide and tenisopide  

4. Camptothecan analgoues: irinotecan and topotecan

1. Vinca alkaloids 

1. Vinca alkaloids:  

Vinblastine: (velban) 

• Vinblastine sulfate is the salt of a dimeric alkaloid from the plant vinca rosa  

• Binds to tubulin and interferes with spindle assembly  

• Resistance conferred by decreased cellular uptake or increased efflux  

• Specific for mitosis but at high concentrations inhibits S and G1  

• Causes nausea and vomiting and leukopenia 

Vincristine: (oncovin)  

• Vincristine sulfate is the salt of a dimeric alkaloid from the plant vinca rosa. 

• Differs from vinblastine in the substitution of an aldehyde for a methyl group 

• Binds to tubulin and interferes with spindle assembly in mitosis  

• Resistance conferred by decreased cellular uptake or increased efflux 

• Cause numbness and tingling of fingers and toes, hair thinning and minimal myelosuppression  

2. Taxol 

• Antimicrotubule agent which inhibits the microtubule structures within the cell  

• Blocks in late G2/M  

Intercalators

• Work by inhibiting topoisomerase  

• Generate stable ternary complex between the DNA, enzyme and the drug – with the DNA strands cleaved so causes starnd cleavage which is less well repaired by cancer cells 

  • Type 1 topoisomerase: campothecin  

  • Type 2 topoisomerase: etoposide  

• Type 2 topoisomerase overexpressed in some resistance 

3. Podophyllotoxins- Etoposide:  

• Semi synthetic alkaloid derived from podophyllotoxin 

• Binds to tubulin but this is not believed to be important for thereputic effect à ay stimulate topoisomerase 2 to cleave DNA  

• Greatest lethality in S and G2 phase 

• Causes leukopenia, alopecia, nausea and vomiting more common with oral administration 

Antibiotics: dactinomycin  

• An antibiotic from a streptomyces species  

• Contains two cyclic peptides which are linked by a chromospore moiety  

• Binds noncovalently to DNA  

• Intercalated between adjacent GC base pairs  

• Inhibits RNA polymerase more than DNA polymerase  

• Resistance conferred by decreased ability of cells to take up or retain the drug  

• Cell cyle stage non specific 

• Causes nausea, vomiting, local vesicat, myelosuppression, redness of skin where radiation has been given, alopecia 

Antiobiotc drugs:  

1. Daunorubicin (daunomycin, rubidomycin) 

2. Doxorubicin (Adriamycin) 

3. Bleomycin (blenoxane)  

1. Daunorubicin  

• An anthracycline glycoside isolated from streptomyces spp  

• Red colour  

• Intercalated between base pairs of DNA and inhibits RNA synthesis  

• Resistance conferred by decreased uptake or more rapid removal or the drug  

• Non specific cell cycle stage  

• Causes nausea, vomiting, myelosuppression, cardiomyopathy, alopecia’ 

Antiobiotc drugs:  

1. Daunorubicin (daunomycin, rubidomycin) 

2. Doxorubicin (Adriamycin) 

3. Bleomycin (blenoxane)  

2. Doxirubicin  

• Same chemical nature as daunorubicin except theres an additional hydroxyl group  

• Same mechanism and side effects as daunorubicin  

• Therapeutic use for leukemias, lymphomas, solid tumours including sarcomas  

Antiobiotc drugs:  

1. Daunorubicin (daunomycin, rubidomycin) 

2. Doxorubicin (Adriamycin) 

3. Bleomycin (blenoxane)  

3. Bleomycin (Blenoxane)  

• Bleomycin sulfate is a mixture of 13 different bleomycin peptides derived from a streptomyces spp.  

• Inhibits DNA synthesis, binds to DNA strands and causes DNA strand breaks 

• Chelates Fe2+ and bonds to DNA where it generates free radicals that degrades DNA  

• Can be inactivated by bleomycin hydrolase so has a spectrum of activity  

• Resistance conferred by increased hydrolase activity, decaresed uptake and increased efflux  

• Increased sensitivity in G2 phase  

• Causes fever, dermatologic reactions, pulmonary toxicity and fibrosis, minimal myelosuppression  

Summary of resistance mechanisms

1. Decrease transport  

2. Gene amplification  

3. Increased DNA repair  

4. Increase in deactivating enzymes 

5. Modified enzymes  

6. Multiple drug resistance à a mechanism to pump out the drug  

• P-glycoprotein (p170)  

• ATP-dependent exporter  

• Broad spectrum of action  

• Overexpressed in resistant cells 

These mechanisms of resistance are different from those in the targeted rug treatment as they try to reestablish survival pathways whereas here the cancer cells are trying to minimise interaction with the drug.  

Combination therapy 

• Mechanism to reduce the dose, increase efficacy or delay the resistance  

• Greater range of side effects but less severe 

Timeline for historical milestones for cancer treatments: