Immunosuppressant/cancer Drugs

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calcineurin inhibitors

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cyclosporine
tacrolimus

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differentiate how cyclosporine and tacrolimus inhibit calcineurin

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cyclosprine binds to cyclophilin
tacrolimus binds to FK-binding protein

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mechanism of action of cyclosporine/tacrolimus

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both inhibit calcineurin, a cyctoplasmic phosphatase. These drugs inhibit the dephosphorylation of NFAT (nuclear factor of activated T-cells) to produce IL-2,3, and IFN-y

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binds FK-binding protein and inhibits IL-2 mediated signal transduction without affecting cytokine production

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sirolimus

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binding of FK-binding protein with this drug inhibits B-cell proliferation and antibody production by blocking cell cycle at G1-S phase

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sirolimus

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adverse effects of cyclosporine

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renal dysfunction (vasoconstrict both afferent and efferent arterioles)
hypertension
neurotoxicity
gum hyperplasia
hypertrichosis

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adverse effects of tacrolimus

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nephrotoxicity
hypertension
neurotoxicity
hyperglycemia

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adverse effects of sirolimus

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hypertriglyceridemia
hepatotoxicity
myelosuppression

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blocks de novo GTP synthesis by inhibiting inosine monophosphate dehydrogenase (only B and T cells because other cells have salvage pathway)

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mycophenolate mofetil

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adverse effects of mycophenolate mofetil

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GI disturbances
myelosuppression, especially neutropenia

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mechanism of action of corticosteroids

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1. altered gene expression leads to decreased synthesis of prostaglandins, leukotrienes, cytokines
2. decrease T-cell proliferation due to decreased IL-2
3. cytotoxic to B and T cells

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binds to T cells and triggers complement-based cytotoxicity

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antithymocyte globulin

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adverse effects of antithymocyte globulin

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serum sickness and anaphylaxis - hypersenstivity reactions
malignancy

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monoclonal antibody that inhibits cytotoxic T cells by binding to CD3

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muromonab-CD3

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adverse effects associated with muromonab-CD3

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anaphylactic reactions
neuropsychiatric effects
hypersensitivity reactions

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used in acute renal allograft rejection

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muromonab

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6 ways to resist anticancer drugs

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1. increased DNA repair
2. formation of trapping agents
3. changes in target enzymes
4. decreased activation of prodrugs
5. inactivation of drugs
6. decreased drug accumulation via MDR1 increased efflux

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drugs that are cell-cycle nonspecific that lead to cross-linked of bases, abnormal base-pairing, and DNA strand breakag

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alkylating agents

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alkylating agents

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cyclophosphamide
mechlorethamine
cisplatin

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alkylating agent associated with nephrotoxicity

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cisplatin

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alkylating agent associated with hemorrhagic cystitis, SIADH, and pulmonary toxicity

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cyclophosphamide

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alkylating agent associated with alopecia and sterility

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mechlorethamine

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inhibits dyhydrofolate reductase

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methotrexate

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adverse effects of methotrexate

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hepatotoxicity

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drug that require activation by HGPRTase

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6-mercaptopurine

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antimetabolite associated with pancreatitis, hepatotoxicity, and myelosuppression

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6-mercaptopurine

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antimetabolite

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methotrexate
5-fluorouracil
6-mercaptopurine

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this antimetabolite inhibits thymidylate synthase and is incorporated into DNA and RNA inhibiting DNA synthesis and RNA processing

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5-fluorouracil

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which part of the cell cycle do antimetabolites primarily act

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S phase

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block the formation of mitotic spindle by prevents assembly of tubulin dimers into microtubules

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vinca alkaloids (vincrinstine)

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adverse effects of vincristine

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peripheral neuropathy

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which part of the cell cycle does vincristine and paclitaxel affect

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M phase

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interferes with mitotic spindle by preventing microtubule disassembly into tubulin monomers

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Paclitaxel

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adverse effects of paclitaxel

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neutropenia and thrombocytopenia
peripheral neuropathy
hypersensitivity reactions

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induces DNA breakage through inhibition of topoisomerase II

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etoposide

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what part of the cell cycle of etoposide affect

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late S and early G2 phases

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actions of doxorubicin

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1. generates free radicals
2. intercalate between base pairs
3. inhibit topoisomerase II
4. block the synthesis of RNA and DNA
5. cause DNA strand scission

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antitumor antibiotic associated with dilated cardiomyopathy

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doxorubicin

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anthracycline (antitumor antibiotic)

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doxorubicin

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antitumor antibiotic that generates free radicals causing DNA strand breaks and inhibiting DNA synthesis; CCS drug active in G2 phase

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bleomycin

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antitumor antibiotic associated with pulmonary fibrosis and hypertensitivity reactions

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bleomycin

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selective estrogen receptor modulator that blocks the binding of estrogen to estrogen-sensitive cancer cells

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tamoxifen

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associated with increased risk of endometrial cancer and thromboembolism

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tamoxifen
agonist activity in the endometrium

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androgen receptor antagonist used in prostatic carcinoma

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flutamide

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GnRH agonist effective in prostatic carcinoma by inhibint release of LH and FSH

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leuprolide

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inhibits tyrosine kinase activity

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imatinib

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drug used for bcr-abl oncogene in CML and c-kit for GIST

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imatinib

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monoclonal antibody against HER-2/neu receptor for epidermal growth factor

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trastuzumab

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adverse effect of trastuzumab

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cardiac dysfunction

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adverse effects of imatinib

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fluid retention with edema
congestive heart failure

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mechanism for L-asparginase

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ALL is not able to synthesis the non essential amino acid asparagine, whereas normal cells are able to do so

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Anti TNF-a drugs

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infliximab
adalimumab
enanercept

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two monoclonal antibodies against TNF-a

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infliximab
adalimumab

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mechanism of axn of etanercept

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recombinant human TNF receptor fused to IgG that binds TNF-a

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adverse effect associated with TNF-a inhibitors

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hypersensitivity reactions
reactivation of latent TB