explain what preclinical studies are
new drug is tested on normal and cancer cell lines in a laboratory setting
-lab investigation involves animal testing for efficacy and toxicity
explain what an investigational new drug (IND) application is
new drug sponsor files an IND application with FDA for clinical testing in humans
-if FDA approves application, clinical trials start
explain what phase I trials are
determine safe and appropriate dose for subsequent studies
- have 10-30 pts with different malignancies that failed standard treatment, and life expectancy of at least 1-2 months with functioning organs capable of drug metabolism and excretion
- highest dose with acceptable toxicity is recommended for PII
explain what phase II trials are
determine effectiveness and side effects of new drug
- have up to 100 pts with same type of malignancy for which no effective treatment is available and/or are most likely to respond to therapy, with life expectancy at least 3 mo and functioning organs with limited number of prior treatments
- patients are closely monitored and immediately removed from treatment if condition worsens
explain what phase III trials are
evaluates effectiveness of new drug, and compares it to best available standard treatment
-large and long-term trials with 100-1000s of patients whose eligibility depends on disease setage, first time treatment, status, goals, etc.
explain what a new drug application is
drug sponsor files NDA or BLA (biologics license application) with FDA
-sponsor submits phase III trial data indicating new drug is safe and superior to standard treatment
explain what FDA approval is
if satisfied with phase III results, FDA approves new drug, which can take ~1.5 years
-after approval, drug can be marketed to public under a label that indicates dosage, safety, indications, and side effects
explain what phase IV trails are
determine long-term safety and effectivfeness of new drug
-since III isn’t long enough to see long-term problems
mechanism of action of Imatinib (Gleevec)
selective activity against Abl tyrosine kinase of CML
-binds to Bcr-Abl at same site where ATP binds, thus blocking Bcr-Abl’s ability to phosphorylate and activate proteins involved in malignant transformation
toxicity of Imatinib (Geevec)
minimal side effects, including nausea, vomiting, fluid retention, muscle cramps, and arthralgia
-myelosuppression in 29% of patients
why was there intrinsic resistance to Imatinib (Gleevec)?
if persistent Bcr-Abl kinase activity, could be due to:
- mutations in Bcr-Abl kinase, making it insensitive to drug
- drug unable to reach target b/c enhanced binding to other proteins in circulation and/or drug efflux
why was there relapse after initial responses to Imatinib?
mostly involves reactivation of Bcr-Abl kinase
-if mutations in Abl kinase, mutant kinase becomes less sensitive to drug
-unknown mechanism behind patients with Bcr-Abl amplification
, or persistent inhibition of Bcr-Abl kinase
what are Nilotinib and Dasatinib?
2nd generation TKIs
- Nilotinib: better fit in ABL pocket (20-30x potency) and more effective if Imatinib-resistant
- Dasatinib: side effect is pulmonary arterial HTN (PAH)
explain what GISTs are
gastrointestinal stromal tumors; most common mesenchymal malignancy of GIT (~1%)
- benign and malignant, but all GISTs are potentially malignant
- commonly stomach > SI > esophagus > colon > rectum
- don’t involve lymph nodes, but metastasize to liver
- generally in older adults
- 90% are KIT (CD117)+, 5% have PDGFRA mutations (both are TK receptors)
how does imatinib treat GIST?
inhibits KIT and PDGFRA at 400 mg/day (although up to 800 mg/d is safe, no better effect)
explain what the Ph+ in CML is
Philadelphia Xm in >90% of cases, that’s a reciprocal translocation between Xm 9 and 22
-t(9,22) fuses BCR gene on Xm 22 with ABL gene from Xm 9, creating famous Bcr-Abl fusion protein
explain what the PML-RARalpha in APL is
reciprocal translocation between Xm 15 and 17 in 98% of cases
-fuses retinoic acid receptor alpha gene with promyelocytic leukemia gene to make PML-RAR-alpha
explain the mechanism of action of retinoic acid in APL
induces terminal differentiation of malignant cells that subsequently undergo natural apoptosis
- in normal cells, RA binds to its receptors including RAR-alpha, to induce expression of genes involved in myeloid cell differentiation
- at pharmacological concentration, RAR-alpha is activated via unknown mechanisms to induce expression of genes involved in myeloid cell differentiation
what is the toxicity of retinoic acid for APL?
if used alone, 1/3 of patients get increased WBC (leukocyte activation/retinoic acid syndrome)
-fever, respiratory distress, weight gain, pleural/pericardial effusion, renal failure
-if concurrent uses of chemo with retinoic acid plus corticosteroids, blocks LAS, but still has dryness of skin/lips, nausea, headache, arthralgia, bone pain
explain what the EGFR family members are
epidermal growth factor receptors in cancer development and progression
- ErbB1 (EGFR, HER1) is activated by EGF, TGF-alpha
- ErbB2 (HER2/neu) has no known ligand, but is the master coordinator that shares the ErbB ligands
- ErbB3 (HER3) is activated by neuregulin
- ERbB4 (HER4) is activated by neuregulin
in which cancers in ErB1 and 2 overexpressed
1: gastric, breast, prostate, bladder, ovarian, colorectal, non-small cell lung, glioblastoma
2: breast, ovarian, gastric
what is trastuzumab’s target? mechanism?
against Erb-B2 (HER-2/neu) growth factor receptor
- seems to prevent transduction of proliferation and survival signals
- induces cytostatic growth inhibitory effects against ErbB2 overexpressing cells, due to Ab-induced downregulation and degradation of receptor
- monotherapy is modest response, but better if combined
what is trastuzumab’s toxicity?
hypersensitivity reaction (even if humanized version)
- ventricular dysfunction and CHF
- can enhance cardiac toxicity of doxorubicin, so give in combo with taxanes
whats the mechanism of cetuximab and against what? its toxicity?
anti-ErbB1 monoclonal Ab
- competes for ligands to inhibit ErbB1 TK activity and growth promoting/survival signals
- works better with cisplatin and other standard chemotherapy agents
- causes pulmonary embolism and allergies
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Unit 1 - Basic Principles of Pharmacology45
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Unit 1 - Volume of Distribution9
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Unit 1 - Biotransformation of toxicants34
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Unit 1 - Pharmokinetics14
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Unit 1 - Drug Administration25
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Unit 1 - Cancer Cherapeutics27
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Unit 1 - Principles of Cancer Chemotherapy68
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Unit 1 - Molecular Targeted Therapy32
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Unit 1 - Pharmacology of Reproduction30
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Unit 1 - Pharmacogenetics and Pharmacogenomics14
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Unit 1 - CYP29
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Unit 2 - Dyshemoglobinemia39
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Unit 2 - Autonomics I30
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Unit 2 - Autonomics II58
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Unit 2 - Autonomics III46
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Unit 2 - Autonomics IV45
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Unit 2 - RA and Gout45
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Unit 2 - Autonomics V63
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Unit 2 - Malaria44
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Unit 2 - Drug Therapy of Inflammation45
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Unit 2 - Antithrombotic Drugs55
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Unit 2 - Histamine, Serotonin, and their Antagonists55
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Unit 3 - CNS: Dopaminergic Drugs62
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Unit 3 - Antiepileptic Drugs27
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Unit 3 - Pharmacotherapy of Primary Headache Syndromes57
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Unit 3 - Ocular Pharmacology54
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Unit 3 - General Anesthetics60
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Unit 3 - Antidepressants25
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Unit 3 - Sedative-Hypnotic Drugs30
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Unit 3 - Local Anesthesia32
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Unit 3 - Narcotic Analgesics43
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Unit 3 - Non-Medicinal Drug Use35
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Unit 4 - Renal Physiology and Diuretics96
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Unit 4 - Asthma/COPD41
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Unit 4 - Review of Heart Physiology47
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Unit 4 - Hypertensives47
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Unit 4 - Coronary Artery Disease51
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Unit 4 - Heart Failure27
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Unit 4 - Anti Arrhythmics59
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Unit 4 - Hyperlipidemia37
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Unit 5 - Treatment of DM29
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Unit 5 - Parathyroids and Bone26
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Unit 5 - Thyroid and Antithyroid Drugs13
