Unit 1 Drugs: Name, Class, Mechanism of action, Therapeutic uses, and Toxicity Flashcards
Combinations: ABVD
Adriamycin (doxorubicin), Bleomycin, Vinblastine, Dacarbazine.
Treats: First Line for Hodgkins Lymphoma
Combinations: CHOP
Cycloposphamide, hydroxydoxorubicin, vincristine (Oncovine), prednisone.
Treats: Non-Hodgkins lymphoma
Combinations: MOPP
Mechlorethamine, vincristine (Oncovine), procarbazine, prednisone.
Treats: Older treatment for Hodgkins Lymphoma
Combinations: CMF
Cycloposphamide, methotrexate, 5-fluorouriacil
treats: older tx for Breast cancer.
Combinations: FEC
5-fluorouracil, epirubicin, Cycloposphamide
Treats: Breast cancer
Name the types of anticancer drugs
alkylating agents antimetabolites DNA Intercalating agents Microtubule inhibitors topoisomerase inhibitors hormones and their antagonists miscellaneous agents
General Mech. of Action for Alkylating Agents
Produce strong electrophiles via the formation of carbonium or ethyleneimonium ion intermediates, which form COVALENT linkages by alkylation of nucleophilic parts present in DNA.
(N7 of Guanine typically)
Alkylating agents have extensive toxicity and substantial potential for resistance.
Yes.
What are the classes of alkylating agents?
Nitrogen mustards
Nitrosoureas
Triazenes
Platinum analogs
What are the Nitrogen Mustards?
Nitrogen mustards are a class of Alkylating agents.
Spontaneously activated in plasma, or via enzymes in liver.
Drugs:
Mechlorethamine
Cyclophosphamide and Ifosamide
Mechlorethamine
Alkylating Agent.
Class: Nitrogen Mustard
Mechanism of action: COVALENTLY bind to DNA via alkylation of nucleophilic portions of DNA.
Therapeutic Uses: Hodgkin’s (part of MOPP), also topically for cutaneous t-cell lymphoma
Toxicity: GI and Bone Marrow (myelosuppression)
Cyclophosphamide and Ifosamide
Alkylating Agent.
Class: Nitrogen Mustard
Mechanism of action: ProDrugs converted to active metabolites via hepatic cytochrome p450 enzymes. COVALENTLY bind to DNA via alkylation of nucleophilic portions of DNA.
Therapeutic Uses:
Cyclophosphamide: most common alkylating agent used. singly or in combination for acute and chronic lymphocytic leukemia, Non-Hodgkin’s, breast, lung, and ovarian cancers.
Ifosfamide: sarcoma and testicular cancer
Toxicity: GI, Bone Marrow Suppression, HEMORRHAGIC CYSTITIS (local irritation of bladder due to toxic metabolite in urine ACROLINE. Give MESNA to counter acroline).
What are the Nitrosoureas?
Nitrosoureas are a class of Alkylating agents.
They are highly lipophilic and can cross the blood brain barrier.
Drugs:
Carmustine and Lomustine
Nitro’sUrea is -mustine, and he’s oily/greasy too(lipophilic).
Carmustine and Lomustine
Alkylating Agent
Class: Nirtosoureas
COVALENTLY bind to DNA via alkylation of nucleophilic portions of DNA. Highly lipophilic, can cross the blood brain barrier, yo.
Therapeutic uses: Brain tumors
Toxicity: profound myelosuppression severe GI RENAL TOXICITY PULMONARY FIBROSIS
What are the Triazenes?
Triazenes are a class of Alkylating agents.
Drugs:
Dacarbazine: prodrug that requires metabolism by cytochromes in liver for activation.
Temozolomide: undergoes nonenzymatic conversion at physiological pH
Dacarbazine and Temozolomide
Alkylating agent
Class: Triazenes
COVALENTLY bind to DNA via alkylation of nucleophilic portions of DNA.
Dacarbazine: prodrug that requires metabolism by cytochromes in liver for activation. (IV administration)
Temozolomide: undergoes nonenzymatic conversion at physiological pH (oral administration)
Therapeutic uses:
Dacarbazine: part of ABVD for Hodgkin’s, also used for malignant melanoma
Temozolomide: malignant gliomas (standard of care + radiation)
Toxicity:
GI
Myelosuppression (neutropenia and thrombocytopenia)
FLU-LIKE SYMPTOMS
What are Platinum Analogs?
Platinum analogs are a class of Alkylating agents.
Only inorganic drugs.
Mech of action: Covalently bind to nucleophilic sites on DNA (NOTE: THEY DO NOT FORM CARBONIUM ION INTERMEDIATES). They react with water to form positively charged intermediates that react with guanine forming an intra- and interstrand cross-links.
Drugs:
Cisplatin
Carboplatin
Oxaliplatin
Cisplatin,
Alkylating agent
Class: Platinum analog
Mech of action: Covalently bind to nucleophilic sites on DNA (NOTE: THEY DO NOT FORM CARBONIUM ION INTERMEDIATES). They react with water to form positively charged intermediates that react with guanine forming an intra- and interstrand cross-links.
Therapeutic uses:
wide range of neoplasms. Testicular, ovarian, cervical, and bladder cancers. Head and neck cancers, lung carcinoma. Often used in combinations.
Toxicity:
Cisplatin: RENAL TOXICITY (RENAL TUBULAR NECROSIS) (a dose limiting toxicity).
ototoxicity (hearing loss)
severe GI
PERIPHERAL MOTOR AND SENSORY NEUROPATHY AT HIGH DOSES
mild/moderate myelosuppression
Carboplatin
Alkylating agent
Class: Platinum analog
Mech of action: Covalently bind to nucleophilic sites on DNA (NOTE: THEY DO NOT FORM CARBONIUM ION INTERMEDIATES). They react with water to form positively charged intermediates that react with guanine forming an intra- and interstrand cross-links.
Therapeutic uses:
ovarian cancer
Toxicity:
Myelosuppression (thrombocytopenia)
Oxaliplatin
Alkylating agent
Class: Platinum analog
Mech of action: Covalently bind to nucleophilic sites on DNA (NOTE: THEY DO NOT FORM CARBONIUM ION INTERMEDIATES). They react with water to form positively charged intermediates that react with guanine forming an intra- and interstrand cross-links.
Therapeutic uses:
gastric and colorectal cancer
Toxicity:
PERIPHERAL SENSORY NEUROPATHY (cold induced acute peripheral neuropathy)
neutropenia
What are the antimetaboiltes?
Structural analogs of Folic acid or of the Purine/Pyrimidine bases.
Mech of Action: they inhibit enzymes required for purine/ pyrimidine synthesis or compete with them in DNA /RNA synthesis. They are therefore Cell Cycle Specific Drugs. (inhibit S phase)
Drugs:
Folate analogs: Methotrexate and Pemetrexed
Pyrimidine analogs: 5-fluorouracil, Cytarabine, Gemcitabine
Purine analog: 6-Mercaptopurine
Methotrexate
Antimetabolite
Class: Folate analog
Mech of action:
folic acid antagonist that inhibits dihydrofolate reductase (DHFR). Therefore, thymidine and purine synthesis is disrupted.
Therapeutic use:
- childhood ALL and Choriocarcinoma
- combination therapy for Burkitt’s lymphoma and breast, ovary, head & neck, and bladder carcinomas.
- Intrathecal use for meningeal leukemia and meningeal metastasis of many cancers
- osteosarcoma
Toxicity: (can be countered with administration of activated form of folic acid called LEUCOVORIN)
myleosuppression, spontaneous hemorrhage
GI
RENAL TOXICITY at high doses. (crystalize in urine and cause renal damage)
HEPATOTOXICITY (long term risk of fibrosis & cirrhosis
defective gamete formation (and spontaneous abortion)
Mech of resistance:
reduced drug uptake
increased production of DHFR
decreased affinity of DHFR for drug.
5-fluoruracil
Antimetabolite
Class: Pyramidine analog
NB: Given IV due to severe GI toxicity and rapid metabolism in gut.
Mech of action:
5-fluoruracil is a pro-drug that is convered inot active metabolites 5-FdUMP and 5-FdUTP. 5-FdUMP inhibits thymidylate synthetase (inhibits T production). and 5-FdUTP is incorporated into RNA and interferes with RNA function.
Therapeutic use:
- In combination therapy for breast, colorectal, gastric, heand & neck, cervical and pancreatic cancer.
- basal cell carcinomas (topical use)
Toxicity:
anorexia and nausea
mucosal ulcerations, stomatitis and diarrhea
myleosuppression
HAND AND FOOT SYNDROME (sensitivity on palms and soles, erythema
CARDIAC TOXICITY (acute chest pain)
Cytarabine (AraC, Depocyt)
Antimetabolite
Class: Pyramidine analog
Mech of Action:
Ara-C converted by deoxycytidine kinase to Ara-CMP –> Ara-CTP; Competes with dCTP and is incorporated into transcribed DNA, terminates DNA synthesis as Ara-CTP
Therapeutics:
AML (most effective treatment), ALL, and blast phase CML
Toxicity:
SEVERE Meylosuppression
GI
Gemcitabine (dFdC, Gemzar)
Antimetabolite
Class: Pyramidine analog
Mech of Action:
Converted to active metabolites: dFdCDP inhibits ribonucleotide reductase (lowers deoxyribonucleotide); dFdCTP incorporates into DNA, terminating DNA synthesis
Therapeutics
Pancreatic cancer
effective against non-small cell lung cancer, ovarian, bladder, esophageal, and head and neck cancer
Toxicity:
Myleosuppression
FLU LIKE SYMPTOMS
6-Mercaptopurine (Purinethol)
Antimetabolite
Class: Purine analog
Mech of Action:
9MP is a Prodrug that is metabolized by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to 6-thioinosinic acid (TIMP)
TIMP:
1. inhibits first step of de novo purine base synthesis
and the formation of AMP and xanthinylic acid from inosinic acid.
2. TIMP is converted to thio-guanine ribonucleotides, inhibiting DNA and RNA synthesis
Therapeutics:
Maintain remission in acute ALL
Toxicity:
myelosuppression
HEPATOTOXICITY IN PROLONGED USE
Resistance:
- reduced metabolism of 6-MP to TIMP due to reduced expression of HGPRT
- Decreased drug transport
