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25 Cards in this Set
- Front
- Back
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Natural Products |
a. Anti-mitotic drugs =Vinca alkaloids, Taxanes.
b. Camptothecin analogues =Topotecan, Irinotecan
c. Antibiotics |
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Tubulin Binding Agents |
Vinca Alkaloids: Inhibition of mitotic spindle formation by binding to tubulin.
Taxanes: Promotes MT formation and inhibit disassembly.
--> Both causes metaphase arrest. |
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Vinca Alkaloids |
*Beneficial effects in DM; later proved to have bone marrow suppression *The extracts contained: Vinblastine, Vincristine. Vinorelbine (synthetic) *Anti-mitotic & anti-microtubule (M phase) *Neurotoxicity by microtubules in brain *Drug resistance -Multi-drug resistance gene (p-glycoprotein) -->Ca channel blocker (eg. verapamil) reverse this -Tubulin mutation or isoform expression
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Effects of Vinca Alkaloids |
Vinblastine = Neurotoxicity (neuropathy, loss of reflexes)
Vincristine = myelosuppression activity (valuable to leukemia and lymphoma)/ SIADH (syndrome of inappprproiate ADH) 나타날 수도 있다.
Vinorelbine: mild neurotoxicity and myelosuppression (intermediate toxicity profile) |
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Taxanes |
eg) Paclitaxel and Docetaxel -Promotes MT polymerization by blocking tubulin diassembly -Solubility 가 떨어져서 ethanol/oil 등의 vehicle 사용하는데 이에 대한 allergic rxn 가능 -->Require pretreatment of histamine receptor antagonist + glucocorticoid (dexamethasone) |
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Taxane Toxicity |
Drug Interaction: -Cisplatin -> paclitaxel result in decreasing the paclitaxel clearance and increased toxicity -Paclitaxel decreases doxorubicin clearance: cardiotoxicity Side Effect: -bone marrow suppression -fluid retention (fluid retention due to docetaxel): pretreatment with dexamethasone relieves fluid retention. |
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Camptothecin |
eg) Topotecan, Irinotecan
Mode of action: Topoisomerase I inhibitor, DNA strand breakage
-Resistance results from decreased expression or mutation of topoisomerase I -Significant hematological toxicity (limited use with other drug like cisplatin) |
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Antibiotics |
-extracted from the fungus Streptomyces -예: Dactionmycin -DNA intercalating agent/ Inhibition of transcription -Inhibition of Topo II / free radical formation (cardiotoxicity) / binds to membranes to alter fluidity and ion transport.
Use: - Children tumor - Choriocarcinoma (used with methotrexate) - Immunosuppressant in renal transplants
Toxicities: Bone marrow suppression, anorexia, nausea, vomiting, GI disturbances
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Anthracycline Antibiotics |
-eg. Doxorubicin, danuorubicin
*mode of action: -Inhibit DNA/RNA synthesis by intercalation -DNA breaks by free radical -Binding to topoisomerase II – double strands breaks'
Toxicities: -Myelosuppression is a major dose-limiting complication -Generate free radicals – irreversible cardiac toxicity a. Cardiomyopathy Acute: cardiac arrhythmia, chronic: heart failure b. Antioxidant or metal chelator reduces cardiotoxicity |
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Cardiac Toxicities by Free Radicals |
-Endogenous superoxide dismutase and catalase play a role in protecting cells from the toxicity -Exogenous iron chelator or antioxidants protects against cardiac toxicity |
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Bleomycin antibiotics |
*Mode of action: DNA breaks by free radical damage (interacting with O2 and Fe2+)
*Toxicities -Minimal myelo- and immunosuppressive -Cutaneous toxicity (hyperpigmentation, hyperkeratosis, ulceration) -Pulmonary toxicity (fibrosis) *Important role in combination therapy *Resistance by expression of a high hydrolase activity |
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L-Asparaginase |
Mode of action -Hydrolyzes L-asparagine to L-aspartic acid, which is essential a.a. to leukemic cells -Resistance arises through induction of asparagine synthetase in tumor cells.
Toxicities: -hypersensitivity by antigenecity -Pancreatitis (insulin deficiency >> hyperglycemia) -Thrombosis (deficient clotting factors such as antithrombin) |
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Glucocorticoids |
eg) Dexamethasone -Marked lympholytic activity -Acute leukemias and lymphomas -Multiple myeloma
*Beneficial effects -Reduction of nausea and emesis -Protection of healthy tissue from cytotoxic side-effects -Reduction of inflammation -Increase appetite, body weight
*Toxicities: chronically used, glucose intolerance, immunosuppression, osteoporosis, muscle wasting, infection |
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Anti-estrogen therapy |
*Block receptor -Selective estrogen-receptor modulators (SERMs): Tamoxifen and toremifene -Selective estrogen-receptor downregulators (SERDs): Fulvestrant
*Decrease ligand: Aromatase inhibitors (AIs) |
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SERM |
Tamoxifen -Competitive partial agonist inhibitor of ER -Blocks ER in breast but mimics estrogen in other tissues (i.e. endometrium)
*Clinical use -ER-positive metastatic breast cancer -Adjuvant therapy after primary tumor excision
*Toxicity -Hot flushes, vaginal bleeding and venous thrombosis -Increased incidence of endometrial cancer (estrogenic)
cf) Toremifene 은 Tamoxifen과 비슷. |
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SERD |
*Fulvestrant -Pure anti-estrogen compound -Devoid of estrogen agonist activity a. 100 times more affinity to ER than tamoxifen b. Down-regulating and degrading the ER c. Long half-life (40 days) – a once-monthly injection d. I. M.
-No risk of endometrial cancer; minimal risk of thromboembolism
-Approved for postmenupausal women who had relapsed/progressed ER-positive metastatic breast cancer despite anti-estrogen therapy |
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Aromatase |
-CYP19 -Highly expressed in placenta and ovary -Peripheral aromatization is an important source of estrogen in postmenopausal women -In premenopausal women, AI activity is overcomed by reflex increase in LH, FSH -In postemenopausal women, no LH/FSH-induced AI activity in peripheral tissue |
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Aromatase Inhibitors (AI) |
1st generation: -aminoglutethimide: inhibits adrenocortical steroid synthesis; non speciic and weak AI.
3rd generation: -3세대 AI 가 가장 많이 쓰인다. Reversible, irreversible 이 두 가지가 존재하고 경구 투여가 가능하다. Irreversible 한 것은 aromatase 에 붙어서 suicide 한다. |
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Complete Androgen Blockade |
=GnRH agonist + AR blockers. |
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Anti-androgens: |
*GnRH agonist: -Leuprolide: 성범죄들한테 사용한다. *GnRH antagonist: -transient suppression of hormone release *Androgen R blocker: -with GnRH agonist, complete androgen blockade.
*Common Side Effect = vasomotor flushing, loss of libido, gynecomastia, increased weight, loss of bone mineral density
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Breast Cancer: therapeutic approach |
–Stage I: surgery alone –Stage II: chemotherapy then chemoprevention with tamoxifen –Stage III/IV: AIs are approved as first-line therapy in HR positive, Combination chemotherapy, Target therapy –trastuzumab, etc. |
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Prostate Cancer |
-Orchiectomy -Estrogen therapy -GnRH agonists -Androgen antagonists -2nd line with chemotherapy |
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Bortezomib (Proteasome Target) |
-Mainly down-regulates NF-κB by inhibition of I-κB degradation -Approved for multiple myeloma (B cell tumor) -Toxicity a. Peripheral neuropathy b. myelosuppression |
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Thalidomide |
-Developed in 1950s for a morning sickness and a sedative -Banned worldwide from babies with no limb -Approved in 1998 again for leprosy -Preclinical and clinical trials in patients with multiple myeloma
*Mode of action -Inhibit monocyte-derived TNF-α -Inhibit angiogenesis (FGF, VEGF) -T cell co-stimulatory activity: immunomodulatory
*Toxicity -Sedation -Peripheral neuropathy C.f. Pre-existing neuropathy or vinca alkaloids/bortezomib |
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VEGF = approve된 것으로 Bevacizumab이 있긴 하지만 잘 사용하지 않는다. |
Adverse Effects -Hypertension: Decreased production of nitric oxide -GI perforation: Infrequent, mechanism unknown -Proteinuria: Disruption of the filtration barrier in kidney -Hemorrhage: Possibly due to the disruption of coagulation system or vascular integrity -Rebound growth when stopped -More invasive and metastatic changes |
