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Log kill hypothesis
Relationship between the time of growth of a cancer colony and the frequency of chemotherapy administration.
Gompertzian kinetics
They rate of growth depends on the size of the tumor. Larger tumors grow more slowly than smaller tumors.
Which drugs work on the M-phase of cell growth?
Vincristine and Vinblastine
What drug is S-phase specific?
Cytarbine
What is a major cause of drug resistance in cancer cells?
Increased production of P-glycoprotein efflux pump that extrudes the drug.
What is MOPP regimen composed of?
Methchlorethamine
Vincristine (oncorin)
Prednisone
Procarbazine
What is adjuvant chemotherapy?
Chemotherapy plus surgery or radiation.
Neoadjuvant therapy.
Chemo plus radiation prior to surgery.
What is the mechanism of action of the alkylating agents?
They form cyclic imonium or carbonium ions that cause alkylation of tissue molecules and DNA.
Mechlorethamine
Strong alkylating agent.
Used in treatment of Hodgkins disease.
Cyclophosphamide
Pro-drug converted into an alkylating agent.
Used in hematologic and solid tumors.
What are the adverse effects of cyclophosphamide?
Hemorrhagic cystitis (can be reduced with mesna)
Chlorambucil
Alkylating agent used in CLL
Melphalan
Alkylating agen used in MM
Carmustine Lomustine
Nitrosoureas.
High lipid solubility
Cross the BBB
Used to treat brain tumors
Streptozocin
Nitrosourea
Used in pancreatic islet cell tumors
What are the three nirtosourea alkylating agents?
Camustine, Lomustine, Sreptozocin
Busulfan
Alkylating agent used in CML
Temozolomide
Alkylating agent used in the treament of brain tumors.
Altretamine
Alkylating agent used in the treatment of ovarian cancer.
Procarbazine
Nonclassical alkylating agent.
Used in Hodgins disease.
May cause myelosuppression and disulfiram like effect.
Dacarbazine
Nonclassical alkylating agent.
Used to treat malignant melanoma.
Bendamustine
Nonclassical alkylating agent.
Used to treat CLL
Cisplatin
Platinum alkylating agent
Inhibits DNA synthesis
Used in testicular carcinoma, ovarian, bladder, lung and head and neck cancers.
What are the adverse reactions caused by Cisplatin?
Nephrotoxicity
Myelosupression
Highly emetogenic
Peripheral neuropathy.
Carboplatin
Platinum alkylating agent
Oxaplatin
Platinum alkylating agent
Methotrexate
Antimetabolite
Inhibits dihydrofolate reductase and the production of tetrahydrofolate.
Used to treat choriocarcinoma, breast cancer and osteosarcoma.
How is resitance to methotrexate developed?
1.Decreased cellular uptake
2. Increased efflux
3. Increased synthesis of DHFR
4. Altered formation of DHFR.
What drug is used to treat overdose of methotrexate?
Leucovorin
Pemetrexed
Converted to polyglutamates in the cell and inhibits DHFR and thymidylate synthase.Used to treat mesothelioma and non-small cell lung cancer.Supplementation of B12 and Folate decrease adverse effects
6-mercaptopurine
Active nucleotides that interfere with reactions in purine synthesis.
Also converted into thiouric acid by xanthine oxidase.
What is the major drug-drug interaction associated with 6-MP?
Allopurinol. Increases uric acid production.
6-Thioguanine
Active nucleotides.
Similar to 6-MP.
Does not have drug reaction with allopurinol.
Fludarabine phosphate
Nucleotide
Inhibits DNA synthesis and repair.
Induces apoptosis.
Used in CLL.
Cladribine
Decreases DNA synthesis and repair.
Used in hairy cell leukemia.
5-flourouracil
Inhibits thymidylate synthase.
Decreases DNA synthesis
Used in colorectal and breast cancer.
Cytarabine
Inhibits DNA synthesis and repair.
Used in AML
May cause myelosupression and neurotoxicity
Gemcitabine
Inhibits DNA synthesis and repair. Inhibits ribonucleotide reductase.
Used in pancreatic cancer and non-small cell lung cancer.
Dactinomycin
Antibiotic drug that is also used to treat cancer.
Intercalates between DNA and prevents RNA synthesis.
Used to treat Wilms tumor
Doxorubicin Daunorubicin
Antiobitics that treat cancer by intercalating between DNA bases, blocking synthesis and causing strand breaks.
What are the side effects associated with doxorubicin?
Main effect is cardiotoxicity. Causes cardiomyopathy related to cumulative dose.
May also cause arrhythmias and myocarditis.
Dexrazoxane
Iron chelator used to counteract the harmful effects of doxorubicin. Prevents formation of free radicals.
Bleomycin
Glycopeptide drug that binds to DNA and causes strand breaks.
Used in testicular carcinomas and lymphomas.
What are the adverse effects caused by bleomycin?
Pulmonary infiltrate (can progress to fibrosis).
Erythema and tenderness of the skin
Allergic reactions
Mitomycin
Reduced to an alkylating agent. Used in squamous cell carcinoma.
May cause myelosupression and hemolytic uremic syndrome.
Vincristine, Vinblastine
Vinca alkloids.
Inhibit tubulin and the polymerization of microtubules in mitotic spindle.
Good vs Hodgkins lymphoma and ALL.
What are the adverse effects caused by vincristine and vinblastine?
Vinblastine - myelosuppression, nausea, vomiting, alopecia
Vincristine - myelosuppression, neurotoxicity, alopecia.
Paclitaxel
Isolated from yew trees.
Binds to and promotes formation of microtubules.
Inhibits mitosis.
Used to treat ovarian and breast cancer.
What are the adverse effects associated with paclitaxel?
Hypersensitivity, myelosupression, peripheral neuropathy.
Docetaxel
Taxane similar to paclitaxel
Used to treat breast cancer.
Etopside
Semisynthetic podophyllotoxin analog
Inhibits topoisomerase II.
Used in testicular and smallcell lung cancers
Topotecan and Irinotecan
Inhibit topoisomerase I causing DNA damage
Topotecan is used for ovarian and small cell carcinoma
Ironotecan used for colorectal cancer.
L-Asparaginase
Enzyme dervided from bacteria that catalyzes hydrolysis of circulating asparagine to aspartic acid and NH3.
Leads to decreased protein synthesis and toxic accumulation of NH3 in the cell.
Used to treat ALL
What are the adverse reacitons caused by L-apsaraginase?
allergic reactions, hepatotoxicity, hemodynamic disorders, neurotoxicity, pancreatitis.
Imatinib (Gleevac)
Inhibits Bcr-Abl tyrosine kinase, active in CML cells.
Dasaitinib, Nilotinib
Inhibits Bcr-Abl and other kinases.
Used in CML that is resistant to imatinib.
Cetuximab, Panitumumab
Monoclonal antibodies that bind to epidermal growth factor receptor and inhibit signaling.
Used in head and neck cancers and colorectal cancer.
What are the adverse effects of cetuximab and panitumumab?
Infusion reaction, acneiform rash, hypomagnesemia, interstitial lung disease.
Gefitinib, Erlotinib
Inhibit tyrosine kinase demain of EGFR.
Used in non-small cell cancer.
Causes diarrhea, acneiform rash and interstitial lung disease.
Bevicizumab
Monoclonal antibody that binds to VEGF.
Used in colorectal cancer and non-small cell lung cancer.
May cause GI perforation, wound healing complications and infusion reactions.
Sorafenib, Sunitinib
Inhibit tyrosine kinases, including VEGF receptors and PDGF-B.
Used in renal cell cancer and hepatocellular carcinoma.
What are the side effects associated with Sorafenib?
Hypertension, fatigue, rash, bleeding, hand-foot syndrome.
Arsenic Trioxide
Induces differentiation.
May cause QT prolongation, arrhythmias.
Used to treat promyleocytic leukemia.
Bortezomib
Proteasome inhibitor
Causes peripheral neuropathy, hypotnesion, thrombocytopenia
Used to treat multiple myeloma.
Hydroxyurea
Inhibits ribonucleotide reductase (enzyme needed in DNA synthesis)
May cause bone marrow suppression and dermatologic reactions
Used in CML