Pharmacology Exam 6

• nitrogen mustards
• ethylenimines
• alkyl sulfonates
• nitrosoureas

molecule has 2 alkyl chloride groups, each has the cl- removed and form an adduct on N7 of guanine causing the DNA to become cross linked

• cyclophosphamide
• ifosfamide

• a prodrug that must be activated by P450
• converted into aldophosphamide which is converted into acrolein and phosphoramide mustard
• both are cytotoxic but phosphoramide mustard is the most active agent

• carmustine
• streptozocin
• no activation by P450 required
• crosses BBB

• cisplatin
• carboplatin

platinum is the reactive molecule that forms an adduct with N7 of guanine which Cl is removed

analog of cisplatin

bone marrow depression with leukopenia and thrombocytopenia

• hemorrhagic cystitis
• reduced by co-administration of MESNA

• ototoxic
• nephrotoxic
• nephrotoxicity can be reduced by chloride diuresis and hydration

hematologic and solid tumors

ovarian cancer

chronic myeloid leukemia

brain tumors

insulin secreting islet cell carcinoma of the pancreas

• folic acid analogs
• purine analogs
• pyrimidine analogs

• methotrexate
• mimic structure of folic acid to disrupt folic acid biosynthesis pathway

• DHFR is the primary site of action
• prevents formation of tetrahydrofolic acid and accumulation of DHF polyglutamate (inhibitory)
• Purine and thymidylate synthesis ceases, stoping DNA and RNA synthesis

• impaired transport into cell
• impaired polyglutamate formation
• increased or altered dihydrofolate reductase
• decreased thymidylate synthase

• at DHFR
• cell can have high levels of DHFR
• cell can have altered DHFR that will not bind MTX

methotrexate

• bone marrow suppression
• nephrotoxicity

leucovorin

sodium bicarbonate to alkalinize urine

• mercaptopurine
• thiguanine
• cladribine
• fludarabine phosphate

• blocks multiple enzymes
• purine compound that contains S which can bind to the enzyme and mymic natrual purines
• inhibits purine biosynthesis

• prodrugs that must be activated
• activated by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to the nucleotide form

• fluorouracil
• cytarabine
• gemcitabine
• capecitabine

inhibits thymidylate synthetase

• metastatic carcinomas of breast and GI tract
• hepatoma
• carcinomas of ovary, cervix, bladder, prostate, pancreas and oropharyngeal areas

B. increased or altered dhfr

• natural compounds
• higher bioavailability
• steady state metabolism
• much safter than other compounds
• not as potent as synthetic compounds, but much less toxicity

• vinca alkaloids
• podophyllotoxins
• camptothecins
• taxanes

• vinblastine
• vincristine

• bind to microtule protine tubulin
• terminates assembly of microtubles
• results in mitotic arrest at metaphase

• n/v
• marrow depression
• alopecia

• systemic hodgkin's disease
• lymphomas

• paclitaxel
• docetaxel
• derived from Yew Tree

enhancement of tubulin polymerization causing unstoppable microtubule growth during m phase

paclitaxel

• neutropenia
• thrombocytopenia
• peripheral neuropathy

• bone marrow suppression
• neurotoxicity
• fluid retention

ovarian and advanced breast cancer

advanced breast cancer

• Anthracyclines
• Dactinomycin
• plicamycin
• mitomycin
• bleomycin

• doxorubicin
• daunorubicin
• similar to napthalene

• High affinity for binding DNA through intercalation
• DNA strand scission via topoisomerase II
• Bind membranes altering fluidity
• Generation of semiquinine free radicle and oxygen radicls which can cleave DNA

• bone marrow depression
• total alopecia
• cardiac toxicity

• carcinomas of breast, endometrium, ovary, testicle, thyroid & lung.
• Eqing's sarcoma and osteosarcoma
• cannot be used with liver problems, will cause toxicity

acute leukemia

• estrogen and androgen inhibitors
• gonadotropin releasing hormone agonists
• aromatase inhibitors

• tamoxifen
• raloxifene
• faslodex

• prodrug that must be activated by CYP2D6
• efficacy could be effected by polymorphisms

• selective estrogen receptor modulator
• antagonist in breast tissue
• agonist in endometrium
• causes the re-expression of a tumor suppressor gene known as maspin, which is repressed in breast cancerous cells.

• hot flashes
• fluid retention
• nausea

• metastatic breast cancer
• patients with estrogen-receptor positive tumors
• potential as preventative therapy in women with breast cancer risk

• aminogluthethimide
• anastrazole

• low dose aromatase inhibitor
• high dose P450 inhibitor

• dizziness
• lethargy
• visual blurring
• rash

ER and PR positive metastatic breast cancer

• asparaginase
• hydroxyurea
• mitoxantrone
• mitotane
• retinoic acid derivatives
• amifostine

• breaks down aparagine to aspartic acid in cancer cells
• asparagine is required for DNA synthesis and cell survival
• neoplastic cells require external sources of asparagine because the levels of aspargine synthetase is reduced

treats childhood acute leukemia

can cause anaphylactic shock

• interferon
• interleukin

• synthesized against foreign molecules/infection
• interfere with cancer cells and stop growth
• encourage killer T cells to attack cancer cells
• encourage cancer cells to send out chemicals that attract the immune system

• kidney cancer
• malignant melanoma
• multiple myeloma
• some leukemia types

• fatigue
• flu like symptoms
• diarrhea
• loss of appetite
• bone marrow effects
• increased infection risk

• monoclonal antibodies specifically bind target cells which stimulate immune system to attack tumor cells
• synthesized from B cells not T cells