Drugs Flashcards
Cyclophosphamide
- Classical drug
- Alkylating agent
- React covalently with DNA
- Most cross-link strands
- Classical toxicities; hemorrhagic cystitis
- Mustard gas
- Metabolized by CypP450
- Used for solid and hematogenous tumors
Folic acid antagonists (methotrexate)
- Classical drug
- Antimetabolite
- Purine and pyrimidine inhibitor
- Inhibits DHFR and carbon transfers needed for purine ring synthesis and dTMP synthesis from dUMP
- Classical toxicities
- Renal and liver toxicity
- Myelosuppression
- Lymphomas and leukemias
Pyrimidine analogs (fluorouracil)
- Classical drug
- Antimetabolites
- Pyrimidine synthesis inhibitor
- Blocks dTMP formation from dUMP
- Classical toxicities
- CNS symptoms (ataxia, confusion)
- Jaundice
- Myelosuppression
- Solid tumors
Purine analogs (6-mercaptopurine)
- Classical drug
- Antimetabolites
- Purine synthesis inhibitor
- Incorporated into DNA when phosphorylated disrupting structure and function
- Classical toxicities
- Myelosuppression
- Childhood ALL and other leukemias and lymphomas
- toxic when used with allopurinol
Vinca alkaloids (vincristine/vinblastine)
- Classical drug
- Mitotic inhibitor
- Bind to tubulin to disrupt microtubule formation resulting in metaphase arrest
- Neurotoxicity, bone marrow hypoplasia
- Myelosuppression
- Peripheral neuropathy
- Lymphoma, sarcoma, solid tumors
Taxanes (paclitaxel)
- Classic drug
- Mitotic inhibitor
- From the bark of yew tree
- Bind to tubulin to disrupt microtubule disassembly resulting in metaphase arrest.
- Myelosuppression
- Peripheral neuropathy
- Cardiac arrhythmia and conduction block
- Breast and ovarian cancers
Topoisomerase inhibitors
- Classical drug
- Binds to topoisomerase
- Endonuclease activity works but ligase activity does not
- End up with a lot of ds DNA breaks
- Could result in secondary leukemias
Cytotoxic antibiotics
- Classical drug
- Intercalate between base pairs and inhibit synthesis
- Generate free radicals that break ds DNA
- Cardiotoxicity
cisplatin/carboplatin
- Classical drug
- Heavy metals
- Cross linking agents
- Used in lung, breast, bladder, GI, ovarian cancers
- Nephrotoxic
- Myelosuppression
- Neuropathy
- ototoxicity
Retinoic acid
- Classical drug
- Used for APL associated with t(15;17)
- Causes DIC but high levels stimulate broken RAR by releasing corepressors
Estrogens, antiestrogens, antiandrogens
- New drug
- Hormone therapy
- Treatment of hormone dependent tumors
- Alter transcription to trigger genetic programs allowing differentiation of tumor cells
- Toxicities: immunosuppression, growth alterations, changes in feminization and masculinization, CV disease
imatinib/Gleevec
- New drug
- Small molecule
- Bcr-Abl TK inhibitor in CML
- Blocks ATP binding site
- Toxicities in GI, Skin, myelosuppression, hepatic, HTN
trastuzumab/Herceptin, bevacizumab/Avastin
- New drug
- Monoclonal antibodies
- Trastuzumab: RhMAb to EGFR subunit HER-2 in breast cancer and induces apoptosis
- Has cardiotoxicity
-Bevacizumab: RhMAb against VEGFR which reduces vascularization of tumor in colorectal cancer, AMD
CAR T cells
- New drug
- Immunotherapy
- Antibodies against CTLA4, PD-1, CD47
- Cancer and autoimmune diseases
New antineoplastics induce apoptosis by acting as
- Signal transduction inhibitors of driver mutations, commonly inhibiting tyrosine or serine/threonine kinases
- Angiogenesis inhibitors
- Antibodies directed against tumor antigens
- CAR T-cells engineered to express tumor antigen receptors
- Antibodies serving as checkpoint inhibitors that sensitize the immune system to tumor neoantigens
Classical antineoplastic drugs induce apoptosis by
- Directly or indirectly inhibiting nucleic acid synthesis and function
- Inhibiting mitotic spindle function
- Inhibiting hormone action
- Miscellaneous mechanisms
Agents that interfere with signal transductio
Tyrosine kinase inhibitors
- Bcr-Abl TKi imatinib (Gleevec), nilotinib, Dasatinib
- EGFR-ERB1 TKi Gefitinib (Iressa), Erlotinib (Tarceva)
Monoclonal antibodies
- EGFR-HER2i Trastuzumab (Herceptin), Pertuzumab (Perjeta)
- VEGFi- Bevacizumab (Avastin)
Checkpoint inhibitors
- Ipilimumab (vs CTLA-4; cytotoxic T lymphocyte associated antigen)
- Pembrolizumab, Nivolumab (vs PD-1; programmed death-1)
Repurposed Classical Drugs
- immunomodulating angiogenesis inhibitors
- Thalidomide, Lenalidomide, Pomalidomide
Classical antineoplastics inhibit nucleic acid synthesis by
Binding directly to DNA and interrupting transcription, replication, repair, and topoisomerase activity
–CCNS: alkylating agents, antineoplastic antibiotics
Acting in pathways to reduce NA synthesis by acting as base analogs that interfere with DNA polymerase or by being incorporated into and damaging DNA
–CCS: antimetabolites (MTX), base analogs (6-MP, 5-FU)
Alkylating agents
- Mechlorethamine, cyclophosphamide
- Busulfan, Carmustine
Antineoplastic antibiotics
Actinomycin D
Adriamycin
Bleomycin
Topoisomerase inhibitors
Epipodophyllotoxins: etoposide
Camptothecins: irinotecan
Antimetabolites
Methotrexate
Purine and pyrimidine analogs
6-mercaptopurine, 5-fluorouracil
Mitotic spindle inhibitors
Vinca alkaloids, taxanes
Agents that alter hormone function
- Estrogen and androgen agonists and antagonists
- GnRH agonists and antagonists
- Aromatase inhibitors
Agents that stimulate differentiation
Retinoic acid
General principles of classic agents
- Act non specifically and cause toxicity to any replicating cell population
- Given in defined courses and combinations to limit toxicity; cannot be given continuously
- Are given with consideration of limiting toxicities
- Careful to consider drug interactions
- Most effect when malignant cells are dividing; if allowed to accumulate the tumors may become resistant
- Kinetic tumor growth can be used to predict dose schedules
- Tumor recurrence is associated with drug resistance
Classic drugs are given in combinations to
- Attack multiple sites
- Avoid toxic overdose of single agent
- Delay resistance
- Synchronize cell growth and application of CCS
Classic toxicities
- Bone marrow suppression
- Ulceration of oral and GI mucosa
- Alopecia, transient sterility
- Impaired wound healing
- Crystalluria due to hyperuricemia
Bleomycin
- Antineoplastic antibiotics
- works in G2
- intercalating agent
- generates free radicals
- interferes with topoisomerase and transcription and replication
- treatment for lymphoma and germs cell, head and neck cancers
- does not cause bone marrow repression
- hyperpigmentations and pulmonary fibrosis
doxorubicin/ daunorubicin
- antineoplastic antibiotics
- intercalating agent that generates free radicals
- interferes with DNA repair, transcription, replication
- induces apoptosis
- used in solid and hematogenous tumors
- cardiotoxic
