Antimetabolites in Chemotherapy

Antimetabolites Overview

• Chemotherapy drugs targeting malignancies.
• Interfere with DNA component formation.
• Cell cycle specific, notably toxic during the S phase.

Common Antimetabolites

• Pyrimidines: Include Cytarabine, Cladribine, Methotrexate, 5-Fluorouracil, Azathioprine, 6-Mercaptopurine, and 6-Thioguanine.
• Purines: Include Hydroxyurea.
• Nitrogenous bases: Cytosine, Thymine, Uracil, Adenine, and Guanine.

Common Side Effects

• Target rapidly dividing cells, leading to myelosuppression.
• Megaloblastic anemia: Results from defective DNA production; common with B12/Folate deficiency and various chemotherapies.
• Severe infections risk if absolute neutrophil count falls below 500 cells/µL indicating neutropenia.

Cytarabine

• Also known as Ara-C or cytosine arabinoside, is a pyrimidine analog.
• Effective primarily in leukemia and lymphomas.
• Adverse effects include myelosuppression and potential neurotoxicity at high doses.

Cladribine

• A purine analog that mimics adenosine.
• Highly toxic to lymphocytes and is the drug of choice for hairy cell leukemia.
• Main adverse effect is myelosuppression.

Methotrexate

• A folate mimic that inhibits dihydrofolate reductase.
• Blocks tetrahydrofolate synthesis necessary for DNA and RNA production.
• Used for solid tumors, leukemia, and autoimmune diseases.
• Side effects include myelosuppression and mucositis.

5-Fluorouracil (5-FU)

• Pyrimidine analog used mainly in colorectal cancer and other solid tumors.
• Inhibits thymidylate synthase, crucial for DNA synthesis.
• Common adverse effects: myelosuppression, nausea, vomiting, mucositis.

6-Mercaptopurine

• Mimics purines and adds to PRPP leading to thioinosinic acid formation.
• Inhibits multiple steps in purine salvage.
• Utilized for immunosuppression in inflammatory bowel disease and organ transplants.

Azathioprine

• A pro-drug converted to 6-Mercaptopurine.
• Used for immunosuppression and shares similar adverse effects.

Hydroxyurea

• Inhibits ribonucleotide reductase.
• Primarily used for polycythemia vera, essential thrombocytosis, and sickle cell disease due to its ability to increase fetal hemoglobin levels.

Alkylating Agents Overview

• Add alkyl groups to nucleotide bases, primarily targeting N7 nitrogen of guanine.
• Cause DNA strand cross-linking leading to replication inhibition.
• Non-specific to the cell cycle.

Nitrogen Mustards

• Include agents like Mechlorethamine, Cyclophosphamide, and Melphalan.
• Often used for solid tumors, lymphomas, and leukemia.

Cyclophosphamide

• Administered both orally and intravenously.
• Requires liver bioactivation and serves as a strong immunosuppressant.
• Notable side effects include myelosuppression and hemorrhagic cystitis.

Ifosfamide

• An isomer of cyclophosphamide, used for germ cell cancer and sarcomas.
• Has a risk of nephrotoxicity and encephalopathy.

Nitrosoureas

• Highly lipid-soluble and can cross the blood-brain barrier, making them effective for brain tumors.
• Example drugs include Carmustine and Lomustine with significant risks like myelosuppression and neurological effects.

Busulfan

• Indicated for myeloablative therapy prior to stem cell transplants.
• Significant side effects: myelosuppression and pulmonary toxicity.

Dacarbazine

• Part of the ABVD chemotherapy regimen for Hodgkin lymphoma.
• Known for causing myelosuppression and other side effects.### Cytotoxic Antibiotics
• Bleomycin can lead to pulmonary fibrosis, presenting with cough, dyspnea, and ground-glass opacities on imaging.
• Vinblastine, a microtubule inhibitor, contributes to restrictive pulmonary function tests (PFTs) and reduced diffusion capacity (DLCO).
• Dacarbazine is classified as an alkylating agent and is part of the MOPP protocol for Hodgkin lymphoma, which includes mechlorethamine, vincristine (Oncovin), procarbazine, and prednisone.

Antitumor Antibiotics

• Derived from Streptomyces bacterial strains, notable examples include anthracyclines, dactinomycin, and bleomycin.
• Key anthracyclines: daunorubicin and doxorubicin (Adriamycin), which act through complex mechanisms including topoisomerase II inhibition, DNA intercalation, and free radical generation.
• Anthracyclines can damage DNA, causing breaks that lead to cell cycle non-specific effects.

Free Radicals and Antitumor Activity

• Free radicals generated by anthracyclines contribute to oxidative damage of DNA and possible cardiotoxic effects.
• Doxorubicin is widely used for breast cancer, various solid tumors, and certain childhood cancers.

Cardiotoxicity of Anthracyclines

• Doxorubicin’s cardiotoxicity arises from free radical damage to myocytes, leading to symptoms like fatigue and edema.
• Monitoring with echocardiograms is necessary after administration, especially in older patients or those with prior pulmonary diseases.
• Dexrazoxane is an iron-chelating agent used to mitigate cardiotoxicity by limiting oxidative stress.

Dactinomycin

• Also known as actinomycin D, it serves several mechanisms including DNA intercalation and RNA synthesis inhibition.
• Primarily used for childhood cancers like neuroblastoma and Ewing’s sarcoma, with myelosuppression as a significant adverse effect.

Bleomycin Clinical Uses and Toxicity

• Effective against lymphomas, germ cell tumors, and certain carcinomas, like squamous cell cancers.
• Skin toxicity due to lower levels of bleomycin hydrolase in skin and lungs leads to conditions like flagellate erythema.
• The primary pulmonary toxicity manifests as pneumonitis, often exacerbated in older patients or those with existing pulmonary conditions.

Microtubule Inhibitors

• Comprised of alkaloids like taxols (paclitaxel and docetaxel) and vinca alkaloids (vincristine and vinblastine).
• Taxols promote microtubule polymerization and disrupt the mitotic spindle, causing cell cycle arrest at the metaphase/anaphase transition.
• Vinca alkaloids inhibit polymerization of tubulin, preventing spindle formation and causing mitotic arrest in metaphase.

Taxol Clinical Uses and Toxicity

• Clinical use for ovarian, breast, lung, head and neck cancers, and solid tumors.
• Common toxicities include hypersensitivity reactions (up to 30% of patients), myelosuppression, and neuropathy.
• Premedication with glucocorticoids and antihistamines can prevent severe allergic reactions.

Vinca Alkaloids

• Effective treatments for breast cancer, lymphomas, and germ cell cancers, utilized in protocols like ABVD for Hodgkin lymphoma.
• Significant neurotoxicity manifests as paresthesias and distal weakness due to loss of axonal transport.

DNA Drugs

• Includes various classes like antitumor antibiotics, alkylating agents, platinum agents, and topoisomerase inhibitors.
• Platinum agents (cisplatin, carboplatin, oxaliplatin) cross-link DNA and are used for solid tumors like lung, esophageal, and ovarian cancers.

Topoisomerase Inhibitors

• Target topoisomerase I (irinotecan, topotecan) and topoisomerase II (etoposide, teniposide).
• Topoisomerase I inhibitors are primarily indicated for colon cancer and ovarian cancer.
• Common toxicity associated with all topoisomerase inhibitors includes myelosuppression and nausea/vomiting.

Antimetabolites Overview

• Chemotherapy drugs targeting malignancies.
• Interfere with DNA component formation.
• Cell cycle specific, notably toxic during the S phase.

Common Antimetabolites

• Pyrimidines: Include Cytarabine, Cladribine, Methotrexate, 5-Fluorouracil, Azathioprine, 6-Mercaptopurine, and 6-Thioguanine.
• Purines: Include Hydroxyurea.
• Nitrogenous bases: Cytosine, Thymine, Uracil, Adenine, and Guanine.

Common Side Effects

• Target rapidly dividing cells, leading to myelosuppression.
• Megaloblastic anemia: Results from defective DNA production; common with B12/Folate deficiency and various chemotherapies.
• Severe infections risk if absolute neutrophil count falls below 500 cells/µL indicating neutropenia.

Cytarabine

• Also known as Ara-C or cytosine arabinoside, is a pyrimidine analog.
• Effective primarily in leukemia and lymphomas.
• Adverse effects include myelosuppression and potential neurotoxicity at high doses.

Cladribine

• A purine analog that mimics adenosine.
• Highly toxic to lymphocytes and is the drug of choice for hairy cell leukemia.
• Main adverse effect is myelosuppression.

Methotrexate

• A folate mimic that inhibits dihydrofolate reductase.
• Blocks tetrahydrofolate synthesis necessary for DNA and RNA production.
• Used for solid tumors, leukemia, and autoimmune diseases.
• Side effects include myelosuppression and mucositis.

5-Fluorouracil (5-FU)

• Pyrimidine analog used mainly in colorectal cancer and other solid tumors.
• Inhibits thymidylate synthase, crucial for DNA synthesis.
• Common adverse effects: myelosuppression, nausea, vomiting, mucositis.

6-Mercaptopurine

• Mimics purines and adds to PRPP leading to thioinosinic acid formation.
• Inhibits multiple steps in purine salvage.
• Utilized for immunosuppression in inflammatory bowel disease and organ transplants.

Azathioprine

• A pro-drug converted to 6-Mercaptopurine.
• Used for immunosuppression and shares similar adverse effects.

Hydroxyurea

• Inhibits ribonucleotide reductase.
• Primarily used for polycythemia vera, essential thrombocytosis, and sickle cell disease due to its ability to increase fetal hemoglobin levels.

Alkylating Agents Overview

• Add alkyl groups to nucleotide bases, primarily targeting N7 nitrogen of guanine.
• Cause DNA strand cross-linking leading to replication inhibition.
• Non-specific to the cell cycle.

Nitrogen Mustards

• Include agents like Mechlorethamine, Cyclophosphamide, and Melphalan.
• Often used for solid tumors, lymphomas, and leukemia.

Cyclophosphamide

• Administered both orally and intravenously.
• Requires liver bioactivation and serves as a strong immunosuppressant.
• Notable side effects include myelosuppression and hemorrhagic cystitis.

Ifosfamide

• An isomer of cyclophosphamide, used for germ cell cancer and sarcomas.
• Has a risk of nephrotoxicity and encephalopathy.

Nitrosoureas

• Highly lipid-soluble and can cross the blood-brain barrier, making them effective for brain tumors.
• Example drugs include Carmustine and Lomustine with significant risks like myelosuppression and neurological effects.

Busulfan

• Indicated for myeloablative therapy prior to stem cell transplants.
• Significant side effects: myelosuppression and pulmonary toxicity.

Dacarbazine

• Part of the ABVD chemotherapy regimen for Hodgkin lymphoma.
• Known for causing myelosuppression and other side effects.### Cytotoxic Antibiotics
• Bleomycin can lead to pulmonary fibrosis, presenting with cough, dyspnea, and ground-glass opacities on imaging.
• Vinblastine, a microtubule inhibitor, contributes to restrictive pulmonary function tests (PFTs) and reduced diffusion capacity (DLCO).
• Dacarbazine is classified as an alkylating agent and is part of the MOPP protocol for Hodgkin lymphoma, which includes mechlorethamine, vincristine (Oncovin), procarbazine, and prednisone.

Antitumor Antibiotics

• Derived from Streptomyces bacterial strains, notable examples include anthracyclines, dactinomycin, and bleomycin.
• Key anthracyclines: daunorubicin and doxorubicin (Adriamycin), which act through complex mechanisms including topoisomerase II inhibition, DNA intercalation, and free radical generation.
• Anthracyclines can damage DNA, causing breaks that lead to cell cycle non-specific effects.

Free Radicals and Antitumor Activity

• Free radicals generated by anthracyclines contribute to oxidative damage of DNA and possible cardiotoxic effects.
• Doxorubicin is widely used for breast cancer, various solid tumors, and certain childhood cancers.

Cardiotoxicity of Anthracyclines

• Doxorubicin’s cardiotoxicity arises from free radical damage to myocytes, leading to symptoms like fatigue and edema.
• Monitoring with echocardiograms is necessary after administration, especially in older patients or those with prior pulmonary diseases.
• Dexrazoxane is an iron-chelating agent used to mitigate cardiotoxicity by limiting oxidative stress.

Dactinomycin

• Also known as actinomycin D, it serves several mechanisms including DNA intercalation and RNA synthesis inhibition.
• Primarily used for childhood cancers like neuroblastoma and Ewing’s sarcoma, with myelosuppression as a significant adverse effect.

Bleomycin Clinical Uses and Toxicity

• Effective against lymphomas, germ cell tumors, and certain carcinomas, like squamous cell cancers.
• Skin toxicity due to lower levels of bleomycin hydrolase in skin and lungs leads to conditions like flagellate erythema.
• The primary pulmonary toxicity manifests as pneumonitis, often exacerbated in older patients or those with existing pulmonary conditions.

Microtubule Inhibitors

• Comprised of alkaloids like taxols (paclitaxel and docetaxel) and vinca alkaloids (vincristine and vinblastine).
• Taxols promote microtubule polymerization and disrupt the mitotic spindle, causing cell cycle arrest at the metaphase/anaphase transition.
• Vinca alkaloids inhibit polymerization of tubulin, preventing spindle formation and causing mitotic arrest in metaphase.

Taxol Clinical Uses and Toxicity

• Clinical use for ovarian, breast, lung, head and neck cancers, and solid tumors.
• Common toxicities include hypersensitivity reactions (up to 30% of patients), myelosuppression, and neuropathy.
• Premedication with glucocorticoids and antihistamines can prevent severe allergic reactions.

Vinca Alkaloids

• Effective treatments for breast cancer, lymphomas, and germ cell cancers, utilized in protocols like ABVD for Hodgkin lymphoma.
• Significant neurotoxicity manifests as paresthesias and distal weakness due to loss of axonal transport.

DNA Drugs

• Includes various classes like antitumor antibiotics, alkylating agents, platinum agents, and topoisomerase inhibitors.
• Platinum agents (cisplatin, carboplatin, oxaliplatin) cross-link DNA and are used for solid tumors like lung, esophageal, and ovarian cancers.

Topoisomerase Inhibitors

• Target topoisomerase I (irinotecan, topotecan) and topoisomerase II (etoposide, teniposide).
• Topoisomerase I inhibitors are primarily indicated for colon cancer and ovarian cancer.
• Common toxicity associated with all topoisomerase inhibitors includes myelosuppression and nausea/vomiting.

This quiz covers the role of antimetabolites as chemotherapy drugs used to treat cancer. It explores how these drugs block the formation of DNA components and their cell cycle specificity. Test your knowledge on this critical aspect of cancer treatment!