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Chemotherapeutic Drugs
Lecture 10/1
89
Medical
Professional
10/01/2013

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Term
What are the 4 principles of giving Drug Combinations?
Definition
1) Each drug should be active alone, 2) The drugs should have Different Mechanisms, 3) The drugs should have Different Toxicities, 4) Cross-resistance should be minimal
Term
What are Cell Cycle Specific Drugs?
Definition
Drugs only active in specific cell cycle phases
Term
What are Cell Cycle Non-specific drugs?
Definition
Drugs that target both resting and dividing cells and so are cytotoxic throughout the cell cycle
Term
What is the general mechanism of Alkylating Agents and what is their cell cylce activity?
Definition
Cell Cycle Non-specific agents that cross-link DNA during all phases of the cell cycle to damage the DNA
Term
What does the Crosslinking of DNA interfere with?
Definition
DNA replication
Term
What are the 4 types of Alkylating Agents?
Definition
Nitrogen mustards, Nitrosoureas, Alkyl Sulfonate, Platinum Complexes
Term
What are the three main Nitrogen Mustards?
Definition
Mechlorethamine, Cyclophosphamide, Ifosfamide
Term
What are the 2 main Nitrosoureas?
Definition
Carmustine, Lomustine
Term
What is the main Alkyl sulfonate?
Definition
Busulfan
Term
What is the main Platinum Complex?
Definition
Cisplatin
Term
What is the most reactive of the nitrogen mustards, and what does it treat?
Definition
Mechlorethamine; treats Hodgkin's lymphoma + many others
Term
How is Mechlorethamine administered?
Definition
IV immediately b/c it is unstable
Term
Toxicology of Mechlorethamine
Definition
NV, BM toxicity
Term
Cyclophosphamide is highly effective vs what cancer?
Definition
Burkitt's lymphoma
Term
How is Cyclophosphamide administered and how does it become activated?
Definition
Orally; it is a Prodrug converted via CP450
Term
Toxicity of Cyclophosphamide
Definition
Cardiotoxic, Hemorrhagic cystitis, Hematuria (bloody urine + bladder burn)
Term
What toxic breakdown product of Cyclophosphamide contributes to Hemorrhagic cystitis, bladder burn, and hematuria, and how is it reduced (inactivated to reduce effects)?
Definition
Acrolein; MESNA is given to reduce levels and prevent hemorrhagic cystitis
Term
How is Ifosfamide administered and activated?
Definition
IV with MESNA; activated via P450
Term
Toxicity of Ifosfamide
Definition
Neurotoxic, Nephrotoxic, Hemorrhagic Cystitis, Hematuria
Term
What are the two Nitrosoureas Carmustine and Lomustine effective against and what is their mechanism?
Definition
Astrocytomas and Metastatic brain tumors; they Inhibit DNA, RNA, and protein Synth
Term
How is Carmustine administered? Lomustine?
Definition
Carmustine via IV; Lomustine orally
Term
Toxicity of Carmustine and Lomustine
Definition
Pulmonary Fibrosis, BM suppression
Term
What is the Alkyl sulfonate Busulfan used against?
Definition
Chronic Myelogenous Leukemia (CML)
Term
Toxicity of Busulfan
Definition
BM suppression
Term
What is the mechanism of the platinum complex Cisplatin?
Definition
Covalently crosslinks GG base pairs by bending DNA
Term
What is Cisplatin effective against (when combined with other particular drugs)?
Definition
Testicular Cancer
Term
Toxicity of Cisplatin
Definition
Renal Damage, Ototoxic, Peripheral sensory Neuropathy
Term
How do Antimetabolites work, what phase are they active in, and what types of tumors are they most effective in treating?
Definition
They are structural analogs of normal molecules; S-phase specific, and they are most effective on rapidly proliferating tumors (leukemias and lymphomas)
Term
What are the 5 Antimetabolites?
Definition
Methotrexate, Mercaptopurine, Fluorouracil, Capecitabine, Cytarabine
Term
Methotrexate, the most widely used Antimetabolite is most effective at treating what two cancers?
Definition
Pediatric Acute Lymphoblastic Leukemia (ALL), and Choriocarcinoma
Term
What is the mechanism of Methotrexate?
Definition
analog of Folic acid, it inhibits Dihydrofolate Reductase to block dTMP synthesis from dUMP (and thus, inhibits DNA synthesis)
Term
What is the role of Dihydrofolate Reductase?
Definition
Methylates Dihydrofolate to form THF
Term
What is the Toxicity of Methotrexate?
Definition
Hepatic Necrosis, BM suppression
Term
What can be given in case of Methotrexate toxicity?
Definition
Leucovorin
Term
What is the Mechanism of Fluorouracil?
Definition
Mimics Uracil and thus inhibits synthesis of Thymidine from Uracil via Thymidilate Synthase
Term
What is the Toxicity of Fluorouracil and how is it administered?
Definition
Severe Ulceration of oral and GI mucosa and thus it is given IV
Term
What drug potentiates the action of Fluorouracil?
Definition
Leucovorin
Term
What is the pharmacological activity of Capecitabine?
Definition
It is a prodrug of Fluorouracil
Term
What is Mercaptopurine used to treat and in what manner?
Definition
Maintenance therapy for Acute Lymphoblastic Leukemia (ALL)
Term
What is the mechanism of Mercaptopurine?
Definition
Inhibits Guanine (purine) synthesis
Term
What is the toxicity of Mercaptopurine?
Definition
BM suppression
Term
What is Cytarabine used to treat?
Definition
AML and ALL
Term
What is the mechanism of Cytarabine?
Definition
It is a Cytosine analog that inhibits DNA chain elongation
Term
What is the toxicity of Cytarabine?
Definition
BM depression
Term
What are the 4 antibotics that are Chemotherapeutic Drugs?
Definition
Doxorubicin, Epirubicin, Dactinomycin, Bleomycin
Term
What is the mechanism of action of Doxorubicin?
Definition
Doxorubicin docks onto the nicked ends of Topoisomerase II to prevent replication
Term
What are the Toxicities of Doxorubicin?
Definition
Red urine (color, not blood hence -rubicin), Severe local tissue damage with extravasation, Cardiac Toxicity, BM suppression
Term
How does Doxorubicin cause cardiac damage (mechanism)?
Definition
Doxorubicin interacts with Fe to generate Hydroxyl radicals that damage myocytes
Term
What is the pharmacology of Epirubicin?
Definition
It is an Analog of Doxorubicin
Term
Toxicity of Epirubicin
Definition
same as Doxorubicin: Red urine, Local tissue damage, BM depression, Cardiac Toxicity
Term
What H2 receptor antagonist used in ulcer therapy will increase the levels of Epirubicin and should be avoided?
Definition
Cimetidine
Term
What is Dactinomycin used to treat?
Definition
pediatric Rhabdomyosarcoma and Wilm's tumor
Term
What is the mechanism of action of Dactinomycin?
Definition
Intercalates between G-C base pairs in DNA to inhibit RNA polymerase and Topoisomerase II
Term
What is the toxicity of Dactinomycin?
Definition
Severe Local tissue damage and necrosis with extravasation
Term
What is the mechanism of Bleomycin (4 steps)?
Definition
1) DNA-Bleomycin-Fe complex forms, 2) DNA-bleomycin-Fe interacts with O2, 3) Superoxide and hydroxyl radicals form, 4) The radicals Fragment DNA
Term
What are the Toxicities of Bleomycin?
Definition
Mild BM depression, Pulmonary Fibrosis
Term
Why does Bleomycin cause Pulmonary Fibrosis?
Definition
Bleomycin is degraded by Hydrolase, which is found only in low levels in the lungs
Term
Of the antibiotics, which is the only one that is cell cycle specific and in which phase is it active?
Definition
Bleomycin; G2 phase
Term
What are the 4 drugs derived from Plants that are Chemotherapeutic drugs?
Definition
Vincristine, Vinblastine, Paclitaxel, and Etoposide
Term
What is Vincristine used to treat?
Definition
Pediatric Leukemia and Adult Lymphomas
Term
What is Vinblastine used to treat?
Definition
Testicular cancer
Term
What is the mechanism of Vincristine and Vinblastine?
Definition
They bind to Tubulin and inhibit their polymerization into microtubules (and are thus mitotic inhibitors)
Term
Vincristine Toxicity
Definition
Mild BM, Sensory neuropathy
Term
Vinblastine Toxicity
Definition
More BM toxic than Vincristine, Less neurotoxic than Vincristine
Term
*What are the only two chemotherapeutic druts that have Mild BM depression?
Definition
Bleomycin and Vincristine
Term
What is the indication for using Paclitaxel and Docetaxel?
Definition
To treat Cisplatin-Resistant Tumors
Term
What is the mechanism of Paclitaxel and Docetaxel?
Definition
Feezes polymerized microtubules to block mitosis in metaphase
Term
What is the toxicity of Paclitaxel and Docetaxel?
Definition
Peripheral sensory Neuropathy
Term
What is the mechanism of Etoposide?
Definition
Inhibition of Topoisomerase II
Term
What are the 4 drugs that inhibit DNA Topoisomerase II?
Definition
Doxorubicin, Epirubicin, Dactinomycin, Etoposide
Term
Toxicity of Etoposide?
Definition
BM depression and Peripheral Neuropathy
Term
What are the 4 drugs that have Peripheral Sensory Neurotoxicity?
Definition
Cisplatin (alkylating agent), Vincristine (plant), Paclitaxel (plant), and Etoposide (plant)
Term
What are Horomone Inhibitors used to treat and what benefit do they have as Chemotherapeutic agents?
Definition
They act on Breast and Prostate tumors (which usually require estrogen/androgen for growth) and they have the benefit of having minor side effects
Term
What are the Two classes and their subclasses of Hormone/Receptor Inhibitors?
Definition
Hormone Inhibitors: Aromatase inhibitors - Receptor Tyrosine Kinase Inhibitors: Chemical agents and Monoclonal antibodies
Term
What are the three Aromatase Inhibitors?
Definition
Exemestane, Letrozole, Anastrozole
Term
What is the mechanism of the Aromatase inhibitors and what cancer in particular do they treat?
Definition
They block the conversion of Androgen to Estrogen, reducing Estrogen levels to treat breast cancer
Term
What are the two main Receptor Tyrosine Kinase Inhibitors that are Chemical Agents?
Definition
Tamoxifen and Imatinib
Term
What is the main therapeutic use of Tamoxifen?
Definition
Estrogen-dependent Breast Cancer
Term
What beneficial side effect does Tamoxifen hve?
Definition
It acts as an agonist of the estrogen receptor in some tissues to reduce serum cholesterol and prevent bone loss
Term
Mechanism of Imatinib and what cancer it is used for
Definition
Inhibits BCR-Abl tyrosine kinase in CML
Term
What are the three Receptor Tyrosine Kinase Inhibitors that are Monoclonal Antibodies?
Definition
Trastuzumab, Cetuximab, and Bevacizumab
Term
What is the mechanism of Trastuzumab and what cancer does it target?
Definition
Inhibits HER2 (Human Epidermal growth factor Receptor 2) in Metastatic Breast Cancer
Term
What is the toxicity of Trastuzumab?
Definition
Cardiomyopathy, infusion reaction
Term
What is the mechanism of Cetuximab
Definition
Monoclonal antibody that binds to/inhibits EGFR and HER1 to inhibit growth and cause apoptosis
Term
What is the target of Cetuximab?
Definition
Metastatic Colorectal Cancer
Term
What is the toxicity of Cetuximab?
Definition
Severe infusion reaction (airway obstruction and hypotension)
Term
What is the mechanism of Bevacizumab?
Definition
Monoclonal antibody that binds to Vascular Endothelial Growth Factor (VEGF) to inhibit angiogenesis
Term
What is the target of Bevacizumab?
Definition
Metastatic Colorectal Cancer
Term
What is the toxicity of Bevacizumab?
Definition
Hypertension, Proteinuria, and Congestive Heart Failure
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