Treatment of cancer Flashcards
To understand why and how DNA is a drug target for the
largest family of anticancer agents.
DNA is a crucial target for many anticancer agents because cancer cells often have altered DNA that drives their uncontrolled growth and proliferation. By targeting DNA, these drugs can disrupt cancer cell division and induce cell death, leading to tumor shrinkage.
The largest family of anticancer agents that target DNA is the class of chemotherapeutic drugs known as the anthracyclines. These drugs, including doxorubicin, daunorubicin, and epirubicin, work by intercalating into the DNA double helix, which means that they insert themselves between the base pairs of DNA. This intercalation distorts the DNA structure, preventing the DNA from replicating properly and interfering with the transcription of genes essential for cell survival.
In addition to intercalation, anthracyclines can also cause DNA damage by generating reactive oxygen species (ROS) and free radicals. These ROS and free radicals can cause breaks in the DNA strands and induce apoptosis, or programmed cell death, in cancer cells.
Anthraclines are also known to interfere with the activity of topoisomerase II, an enzyme that is essential for DNA replication and repair. By inhibiting topoisomerase II, anthracyclines can cause double-stranded DNA breaks, leading to cell death.
Overall, the ability of anthracyclines and other DNA-targeting drugs to interfere with the structure and function of DNA is a key reason why they are effective against many types of cancer. However, these drugs can also cause significant side effects due to their impact on healthy cells, particularly those with high rates of cell division such as hair follicles and blood cells. Therefore, the use of these drugs must be carefully managed and balanced with the potential benefits for the patient.
To be familiar with the various categories of both synthetic
and naturally-occurring DNA-interactive
cancer chemotherapeutic agents with respect to their mechanisms of
action (MOA).
Alkylating agents: These drugs, including cyclophosphamide, busulfan, and cisplatin, work by adding alkyl groups to DNA, which can cause DNA cross-linking and damage that leads to cell death.
Antimetabolites: These drugs, including methotrexate, 5-fluorouracil, and cytarabine, interfere with the synthesis of nucleic acids by mimicking or inhibiting the action of key metabolic enzymes, which can lead to DNA damage and cell death.
Topoisomerase inhibitors: These drugs, including etoposide, doxorubicin, and irinotecan, work by interfering with the action of topoisomerases, enzymes that regulate the coiling and uncoiling of DNA during cell division. Inhibition of topoisomerases can lead to DNA strand breaks and cell death.
DNA intercalators: These drugs, including doxorubicin, daunorubicin, and mitoxantrone, intercalate themselves between DNA base pairs and can cause DNA damage, including single-strand and double-strand breaks, that leads to cell death.
DNA cross-linking agents: These drugs, including nitrogen mustards, cisplatin, and mitomycin, cross-link DNA strands, leading to DNA damage and cell death.
Natural products: Many naturally-occurring compounds, such as paclitaxel (derived from the Pacific yew tree), vinblastine (from the Madagascar periwinkle), and camptothecin (from the Chinese Happy tree), have been found to have anticancer activity. These compounds often have unique mechanisms of action, such as inhibition of microtubule formation, and can lead to DNA damage and cell death.
To be able to quote an example of one member from each
family and to be familiar with its chemical structure (and SAR
where appropriate). for chemotherapeutic agents
Alkylating agents: Cyclophosphamide is an example of an alkylating agent. Its chemical structure includes a cyclophosphamide group (a nitrogen mustard) linked to a propanolamine side chain. The drug is activated in the liver to form active metabolites, such as phosphoramide mustard, which can alkylate DNA.
Antimetabolites: Methotrexate is an example of an antimetabolite. Its chemical structure includes a folic acid analog with a glutamate tail. Methotrexate inhibits dihydrofolate reductase, an enzyme involved in the synthesis of nucleotides, leading to reduced DNA synthesis and cell death.
Topoisomerase inhibitors: Etoposide is an example of a topoisomerase inhibitor. Its chemical structure includes a quinoline ring and a glycoside moiety. Etoposide binds to topoisomerase II, preventing the enzyme from resealing DNA strands during replication, leading to DNA strand breaks and cell death.
DNA intercalators: Doxorubicin is an example of a DNA intercalator. Its chemical structure includes an anthracycline ring system and a sugar moiety. Doxorubicin intercalates between DNA base pairs, disrupting DNA replication and transcription and leading to DNA damage and cell death.
DNA cross-linking agents: Cisplatin is an example of a DNA cross-linking agent. Its chemical structure includes a platinum atom linked to two chloride ions and two amine groups. Cisplatin forms covalent bonds with the purine bases in DNA, leading to DNA cross-linking and ultimately cell death.
Natural products: Paclitaxel is an example of a natural product. Its chemical structure includes a taxane ring system and a side chain. Paclitaxel stabilizes microtubules during cell division, preventing the formation of the mitotic spindle and ultimately leading to cell death.
For each category of agents within the family, to understand
how the molecules interact with DNA, and how this may lead
to anticancer activity.
Alkylating agents:
Alkylating agents interact with DNA by adding alkyl groups (e.g., methyl or ethyl groups) to the DNA molecule. These groups can bind to nucleophilic sites in the DNA, such as the nitrogen atoms of purine or pyrimidine bases, or the phosphate group of the DNA backbone. The alkyl group is then transferred to the DNA molecule, leading to the formation of covalent bonds between the drug and the DNA. This covalent modification of DNA can interfere with DNA replication and transcription, leading to DNA damage that can trigger cell death. Alkylating agents can also cause DNA cross-linking, in which two strands of DNA are covalently linked together, preventing DNA replication and causing cell death.
Antimetabolites:
Antimetabolites are structurally similar to endogenous metabolites required for DNA synthesis and repair. They can competitively inhibit enzymes involved in the synthesis of nucleotides, such as dihydrofolate reductase or thymidylate synthase. By inhibiting nucleotide synthesis, antimetabolites can interfere with DNA replication and repair, leading to cell death.
Topoisomerase inhibitors:
Topoisomerase inhibitors interact with topoisomerases, which are enzymes that regulate DNA topology during replication and transcription. These drugs can inhibit the activity of topoisomerase I or II, preventing the enzyme from resealing DNA strands during replication or transcription, leading to DNA strand breaks and cell death.
DNA intercalators:
DNA intercalators can insert themselves between the base pairs of the DNA molecule, leading to the distortion of the DNA helix. This can interfere with DNA replication and transcription, leading to DNA damage and cell death.
DNA cross-linking agents:
DNA cross-linking agents can bind covalently to the purine or pyrimidine bases of DNA, leading to the formation of DNA adducts. This can cause DNA cross-linking, in which two strands of DNA are covalently linked together, preventing DNA replication and causing cell death.
Natural products:
Natural products can act through a variety of mechanisms, such as binding to microtubules, which are involved in cell division, and inhibiting their function. This can prevent the formation of the mitotic spindle and ultimately lead to cell death. Natural products can also inhibit enzymes involved in DNA replication and transcription, leading to DNA damage and cell death.
