TBL 9 - Cancer Chemotherapy Primer Flashcards
What is HER-2/neu (erbB-2)?
A growth factor receptor.
What is ras?
A signal transduction molecule.
What is myc?
A transcription factor.
What is src?
A protein tyrosine kinase.
What is hTERT?
An enzyme that functions in DNA replication.
What is Bcl-2?
A membrane associated protein that functions to prevent apoptosis.
What is ABL?
A nonreceptor tyrosine kinase.
What is chemotherapy?
A drug treatment that uses powerful chemicals to kill fast-growing cells in the body and is most often used to treat cancer.
What is immunotherapy?
A form of cancer treatment that uses the power of the body’s own immune system to prevent, control, and eliminate cancer.
What is an example of genetic alterations in colon carcinoma?
1) APC is inactivated early in tumor development.
2) Mutations of rasK frequently occur and are found in early-stage adenomas.
3) Mutations in MADR2 and p53 are associated with later stages.
What areas of cells are particularly affected by cytostatic agents?
Cells in the bone marrow, GI tract, gonads, hair follicles, and skin.
(Rapidly dividing cells).
What drugs exert their actions on the S phase of the cell cycle?
- Cytarabine
- 6-mercaptopurine
- 6-thioguanine
- 5-fluorouracil
- Methotrexate
- Hydroxyurea
- Irinotecan (blocks topoisomerase I)
- Etoposide (blocks topoisomerase II)
What drugs exert their actions on the G2 phase of the cell cycle?
- Bleomycin
- Bortezomib
What drugs exert their actions on the M phase of the cell cycle?
- Vinblastine
- Vincristine
(Blocks tubular polymerization) - Paclitaxel (Blocks depolymerization of microtubules)
What drugs exert their actions on the G1 phase of the cell cycle?
- Asparaginase
- -tinibs
What drugs are non-cell-cycle specific?
- Alkylating agents (cyclophosphamide, cisplatin, and procarbazine)
- Antitumor antibiotics (doxorubicin and Daunorubicin)
- Nitrosoureas (lomustine and carmustine)
When are cell-cycle specific drugs most effective and when are non-cell-cycle specific drugs most effective?
CCS drugs are most effective in high growth fraction tumors while CCNS drugs are more useful in low growth fraction solid tumors.
Define “log kill.”
Using first order kinetics, a given dose of drug will destroy a constant fraction or proportion of a cell population rather than a constant number of cells.
Will kill a fixed percentage of tumor cells, not a fixed number.
What clinical setting is primary induction therapy used?
Treatment of hematologic cancers and advanced solid tumors of which no alternative treatment exists.
Before surgery.
What clinical setting is neoadjuvant chemotherapy used?
Chemotherapy in patients with localized cancer with alternative therapy such as surgery.
Before surgury.
What clinical setting is adjuvant chemotherapy used?
Chemotherapy of many solid tumors adjuvant to local treatment such as surgery or radiation.
After surgery.
What is included in the ABVD regimen and what is it used for?
Doxorubicin (Adriamycin), Bleomycin, Vincristine, Dacarbazine, and Prednisone.
Used to treat Hodgkin’s Lymphoma
What is included in the CHOP regimen and what is it used for?
Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone plus Rituximab.
Used to treat Non-Hodgkin’s Lymphoma.
What combination of drugs is used to treat Acute Lymphocytic Leukemia (ALL) in children?
Prednisone, Vincristine, and Asparaginase or an anthracycline, plus Intrathecal Methotrexate.
What combination of drugs is used to treat breast cancer?
Cytotoxic agents, hormonal therapy with tamoxifen or an aromatase inhibitor (anastrozole), and Trastuzumab.
What combination of drugs is used to treat Acute Myelogenous Leukemia (AML) in adults?
Cytarabine and Idarubicin or Daunorubicin.
What combination of drugs is used to treat Chronic Myelogenous Leukemia (CML)?
Imatinib and Interferon
What combination of drugs is used to treat colon carcinoma?
Fluorouracil, Leucocorvin, and Oxaliplatin
What combination of drugs is used to treat ovarian cancer?
Paclitaxel and Carboplatin
What combination of drugs is used to treat pancreatic cancer?
Gemcitabine and Erlotinib
What combination of drugs is used to treat prostatic carcinoma?
GnRH Agonist or Antagonist and an Androgen Receptor Antagonist.
What combination of drugs is used to treat lung carcinoma?
Carboplatin, Paclitaxel, and Bevacizumab.
What main group are the alkylating agents cyclophosphamide and mechlorethamine part of?
Nitrogen mustards
What main group is the alkylating agent Carmustine part of?
Nitrosoureas
What main group is the alkylating agent Busulfan part of?
Alkyl Sulfonate
What hepatic mechanism does cyclophophamide require in order to be converted to its active form?
CYP450
What is the MOA of Alkylating Agents?
Attaches an alkyl group to N7 of the purine base guanine, cross-linking DNA and creating ring cleavage.
What is the toxic metabolite of cyclophosphamide?
Acrolein
What is acrolein responsible for in terms of adverse effects?
Hemorrhagic cystitis with symptoms of suprapubic pain, hematuria, and cystoscopy findings.
NVD, depression of BC counts, loss of appetite, and alopecia.
What is used to prevent hemorrhagic cystitis caused by acrolein (cyclophosphamide)?
MESNA (mercaptoethanesulfonate)
What is the MOA of procarbazine?
A reactive agent that forms hydrogen peroxide , which generates free radicals that cause DNA strand scission.
What are the adverse effects of procarbazine?
- Myelosuppression
- GI irritation
- CNS dysfunction
- Peripheral neuropathy
- Skin reactions
- Disulfiram-like reactions
What is the MOA of the nitrosoureas Carmustine, Lomustine, and Semustine and what is their clinical application?
Acts by cross-linking (DNA alkylation) and is highly lipid soluble, allowing for it to cross the BBB which is useful for the treatment of CNS cancers.
Can temozolomide penetrate the CNS?
Yes
What are the toxic effects of Busulphan?
- Adrenal insufficiency
- Skin pigmentation
- Acute liver injury
- Pulmonary fibrosis
- Alveolar hemorrhage (“Bulsulphan Lung”)
What are the toxic effects of Melphalan?
Multiple myeloma
What drugs are included in the MOPP regimen?
- Mechlorathamine
- Oncovin
- Procarbazine
- Prednisone
What drugs are considered platinum-based chemotherapeutic agents?
Cisplatin, Carboplatin, and Oxaliplatin
What is the MOA of platinum-based chemotherapeutic agents?
Damages DNA by binding at N7 of guanine and causing DNA crosslinking.
What are platinum-based chemotherapeutic agents used for?
Testicular, bladder, lung, and ovarian cancers.
What are the toxic effects of platinum-based chemotherapeutic agents?
- Neurotoxicity
- Nephrotoxicity (can be prevented with adequate hydration and diuresis)
- Ototoxicity (hearing loss)
- Highly emetic (induces vomiting)
What drug protects against renal toxicity caused by cisplatin?
Amifostine
What 4 drugs are considered to be antitumor antibodies?
1) Bleomycin
2) Mitomycin
3) Anthracyclines - Doxorubicin and Daunorubicin
What are the MOAs for the anthracyclines (Doxorubicin and Daunorubisin)?
- Inhibits topoisomerase II to cleave DNA
- Binds with iron to generate free radicals
- Causes intercalating between base pairs
- Induces histone eviction from the chromatin
Overall, inhibits DNA and RNA synthesis.
What are the uses of anthracyclines (doxorubicin and daunorubicin)?
- Breast, lung, endometrial, and ovarian cancer
- Part of the ABVD regimen for Hodgkin’s lymphoma
- ALL
- Multiple myeloma
- Non-Hodgkin lymphoma
What are the adverse effects of anthracyclines (doxorubicin and daunorubicin)?
- Bone marrow suppression
- Cardiotoxicity (dilated cardiomyopathy and congestive heart failure)
- Alopecia
What medication is used to protect against cardiotoxicity caused by the anthracyclins?
Dexrazoxane
What is the MOA of Dexrazoxane?
Binds free iron or removes iron from the doxorubicin-iron complex, thereby preventing oxygen free radical formation
What phase of the cell cycle does Bleomycin act on?
G2 Phase
What is the MOA of Bleomycin?
- Intercalates DNA via an iron-bleomycin complex that produces free radicals causing DNA single and double strand breaks.
When is Bleomycin used?
- Included in the ABVD regimen for Hodgkin’s lymphoma.
- Also used to treat Non-Hodgkin’s lymphoma, and testicular, head, neck, and skin cancers.
What are the adverse effects of Bleomycin?
- Pneumonitis
- Pulmonary fibrosis (cough, dyspnea, crackles, infiltrates on chest x-ray)
- Low bone marrow suppression
What phase of the cell cycle does Methotrexate act on?
S phase
What type of drug is methotrexate?
Antimetabolite
What is the MOA of Methotrexate?
DNA synthesis inhibitor.
Inhibits dihydrofolate reductase which inhibits the conversion of folic acid to reduced folate cofactors, which in turn inhibits thymidylate synthesis.
Also, reduces T cell proliferation.
What is Methotrexate used for?
- Leukemias
- Lymphomas
- Breast cancer
- Rheumatoid arthritis
- Psoriasis
- Immunosuppressant
- Ectopic pregnancies -> Abortion
What are the adverse effects of Methotrexate?
- Bone marrow suppression
- Hepatotoxicity
- Aphthous ulcers
- Renal and GI upset
What drug is used to circumvent the blocked tetrahydrofolate synthesis caused by Methotrexate?
Leucovorin
What is the MOA of Leucovorin?
Supplies reduced folate directly, bypassing the metabolic block caused by Methotrexate.
What is another name for Leucovorin?
Folinic acid-N5-formyl-FH4
What type of drug is 5-fluourouracil (5-FU)?
A pyrimidine analogue and prodrug that is included in the antimetabolite group.
What is the MOA of 5-FU?
5-FU is converted into an abnormal dUMP (5-FdUMP) which is an irreversible inhibitor of thymidylate synthase, inhibiting the formation of thymine causing cellular death.
Inhibits DNA synthesis and inhibits RNA processing.
What part of the cell cycle does 5-FU act on?
S phase
What effect does Leucovorin have on 5-FU?
Increases the efficacy of it.
What is 5-FU used for?
Breast, ovarian, colon, head, and neck cancers.
What are the adverse effects of 5-FU?
- Bone marrow suppression
- Neurotoxicity
- NVD
- Mucositis
- Cerebral ataxia
- Coronary vasospasm
What type of drug is 6-Mercaptopurine (6-MP)?
Purine analog
How are azathioprine and 6-MP related?
Azathioprine is the prodrug of 6-MP.
What is the MOA of 6-MP?
Inhibits numerous enzymes of purine nucleotide conversion, inhibiting purine, DNA, and RNA synthesis.
What compound does 6-MP need to be converted to in order to be active and what compound metabolizes this action?
6-MP must be metabolized by hypoxanthine guanine phophoribosyl transferase (HGPRT) to 6-thioinosinic acid.
How do some cancer cells have resistance to 6-MP?
They have a decreased activity of HGPRT.
Where is 6-MP metabolized and what is it metabolized by?
Metabolized in the liver by xanthine oxidase.
What drug does 6-MP interact with that causes 6-MP to be less effective?
Allopurinol
What drug class does 6-MP interact with that causes 6-MP toxicity?
Thiopurines
What is 6-MP used for?
- Childhood acute lymphocytic leukemias
- Chronic myeloid leukemia
What are some adverse effects caused by 6-MP?
- Bone marrow suppression
- Hepatic dysfunction (cholestasis, jaundice, and necrosis)
- Mucositis
- Diarrhea
What kind of drugs are Gemcitabine and Cytarabine?
Pyrimidine analogs
What is the MOA of Gemcitabine?
Is a fluorinated cytidine analog that acts on the S-phase of the cell cycle and is an inhibitor of DNA synthesis.
What is Gemcitabine used for?
- Pancreatic carcinoma
- Non-small cell lung cancer
- Breast and ovarian cancers
What are some adverse effects of Gemcitabine?
- Myelosuppression
- Oral and GI ulceration
- NV
- High doses can damage the liver, heart, and other organs.
What is the MOA of Cytarabine?
Activated by kinases to AraCTP which inhibits DNA polymerase and incorporates itself into DNA and RNA.
What are some adverse effects of Cytarabine?
- NV
- Myelocuppression
- Neutropenia
- Thrombocytopenia
- Cerebellar ataxia
What is Cytarabine used for?
- AML
- ALL
- CML in blast crisis
What type of drug is Hydroxyurea?
Antimetabolite
What is the MOA of Hydroxyurea?
Inhibits the ribonucleotide reductase enzyme and shifts globulin gene transcription from beta to gamma, which increases the levels of HbF and decreases HbB.
What is Hydroxyurea used for?
Sickle cell disease.
Fetal hemoglobin is not affected by the sickle cell mutation.
What are some adverse effects of Hydroxyurea?
- Myelosuppression
- Megaloblastic anemia
- Pancytopenia
What type of drug is all-trans retinoic acid (ATRA)?
Differentiating agent
What is the MOA of ATRA?
Promotes differentiation of promyelocytes.
What is ATRA used for?
Acute promyelocytic leukemia
What are some adverse effects of ATRA?
- “Differentiation syndrome” with respiratory distress
- Pleural and pericardial effusions
- CNS symptoms
What is the MOA of vinblastine and vincristine?
Binds to B-tubulin and causes inhibition of microtubular polymerization in the M phase of the cell cycle.
What is vinblastine used for?
ABVD protocol for Hodgkin lymphoma.
What is vincristine used for?
Hodkin lymphoma, AL leukemias, Wilms tumor, rhabdomyosarcoma, neuroblastoma, and breast cancer.
What are the side effects of vinblastine and vincristine?
- BMS
- Neurotoxicity (loss of axonal transport, paresthesia/pain in fingers and feet, and distal weakness)
What is the MOA of the taxanes (Paaclitaxel and Docetaxel)?
- Blocks microtubule breakdown or degradation
- Enhances tubulin polymerization
- Hyperstabilizes microtubules in the M phase
What adverse effects are caused by the taxanes?
- Peripheral neuropathy (burning paresthesia of hands and feet)
- Myelosuppression
- Hypersensitivity
What is Paclitaxel used for?
- Ovarian cancer
- Non-small cell lung cancer
- Breast cancer
What is Docetaxel used for?
- Breast cancer
- Non-small cell lung cancer
What is Cabazitaxel used for?
Hormone refractory prostate cancer.
What is the MOA of the Camptothecon class (irinotecan and topotecan) of DNA topoisomerase inhibitors?
Inhibits topoisomerase I which normally breaks single strands of DNA before resealing.
What are the pharmacokinetics of irinotecan?
Irinotecan is a prodrug that is activated in the liver to SN-38 and eliminated in the bile and feces.
What are the pharmacokinetics of Topotecan?
It is eliminated renally.
What are Irinotecan and Topotecam used for?
Colon, ovarian, and small cell cancer.
What is the adverse effect of Topotecan?
Myelosuppression
What is the adverse effect of Irinotecan?
Diarrhea
How is Irinotecan toxicity treated?
- Acute: diarrhea
- Delayed: loperamide which acts on the mu-opiod receptors in the mesenteric plexus of the large intestine
What is the MOA of the Epipodophyllotoxins class (etoposide and teniposide) of DNA topoisomerase inhibitors?
Inhibits topoisomerase II which normally breaks double strands of DNA before resealing.
What are the pharmacokinetics of Etoposide?
It is eliminated renally and dose reductions should be made in patients with renal impairment.
What are the clinical uses of etoposide and teniposide?
Used in combination drug regimen for therapy of lymphoma, lung, germ cell, and gastric cancers.
What are the adverse effects of etoposide and teniposide?
- Myelosuppression
- GI upset
- Alopecia
What mechanism of resistance do cancer cells have against alkylating agents and cisplatin?
Increased DNA repair.
What mechanism of resistance do cancer cells have against Bleomycin, Cisplatin, and the Anthracyclines?
Formation of trapping agents.
What mechanism of resistance do cancer cells have against Methotrexate?
Changes in target enzymes.
What mechanism of resistance do cancer cells have against the purine and pyrimidine antimetabolites?
Decreased activation of prodrugs and inactivation of anticancer drugs.
What mechanism of resistance do cancer cells have against Bleomycin and Vincristine?
Decreased drug accumulation via increased expression of MDR1 for the cell surface glycoprotein P-glycoprotein which is involved in the accelerated efflux of the drugs.
What is tumor lysis syndrome?
An oncologic emergency that is caused by massive tumor cell lysis and the release of large amounts of potassium, phosphate, and uric acid into the systemic circulation ;eading to deposition of uric acid and/or calcium phosphate crystals in the renal tubules and acute kidney injury, oliguria, or anuria.
What are some risk factors for tumor lysis syndrome?
Burkitt lymphoma and ALL.
What agent is used to treat tumor lysis syndrome?
Rasburicase with correction of electrolyte abnormalities.
Also Allopurinol and febuxostat.
What can be used prophylactically for tumor lysis syndrome?
IV hydration and urinary alkalinization.
What is the MOA of Rasburicase?
Causes a reaction with an enzyme that turns uric acid into the inactive substance Allantoin which reduces uric acid levels.
