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65 Cards in this Set

  • Front
  • Back
Pt tx w chemo for Hodgkins develops symptoms of schizophrenia - which drug?
1. vincristine
2. nitrogen mustard
3. prednisone
4. combination or another drug
PREDNISONE = CNS toxicity = psychosis

vincristine = neurotoxicity (areflexia, peripheral neuritis) limits usefulness

nitrogen mustards = alkylate DNA
-- M2C2 = mechlorethamine, melphalan, cyclophosphamide, chlorambucil
Cancer cells lacking hypoxanthine-guanine phosphoribosyl transferase (HGPRTase) are resistant to ?
6-mercaptopurine and 6-thioguanine

-- The enzyme HGPRTase converts 6-MP and 6-TG to a nucleotide form which inhibits purine synthesis and thus blocks DNA/RNA synthesis
Cyclophosphamide used to treat non-Hodgkins lymphoma, breast and ovarian carcinomas. MOA?
activated by CYP450 to a metabolite which covalently x-links DNA strands at guanine N-7
Cyclophosphamide S/E’s?
1. causes sterile hemorrhagic cystitis

2. alkylating agents like cyclophosphamide can cause myelogenous (granulocytic) leukemia
Patient to be treated w chemo w cyclophosphamide. but is already receiving a drug for gout. Which gout drug would increase the toxicity of cyclophosphamide?
allopurinol prolongs the half-life of cyclophosphamide, but MOA is unknown
Drug interactions with allopurinol?
1. alluopurinol inhibits xanthine oxidase to prevent the formation of uric acid)

2. allopurinol often used after tx of hematologic cancers to prevent hyperuricemia after tumor cell lysis

3. allopurinol inhibits the metabolism of 6-mercaptopurine (6-MP) by xanthine oxidase, so need to reduce dose of 6-MP to 25% of normal dose in patients on allopurinol

4. Need to↓ dose of immunosuppressive drug azathioprine by 25% of normal when given to a patient taking allopurinol because azathioprine is metabolized to 6-MP
Drugs which interfere w microtubule function?
paclitaxel (taxol)

Vinblastine binds to tubulin and blocks the ability of tubulin to polymerize into microtubule = mitotic arrest in metaphase
Paclitaxel MOA?
binds to microtubules of mitotic spindle to hyperstabilize them so that they cannot break down in anaphase, get mitotic arrest
Paclitaxel therapeutic use?
ovarian and breast cancer
Dactinomycin MOA?
binds tightly to double-stranded DNA between G-C pairs to inhibit all forms of DNA-dependent RNA synthesis, esp. mRNA synthesis
Dactinomycin therapeutic use?
Wilm’s tumor
Doxorubicin and Daunorubicin MOA?
Anthracycline antibiotics

intercalation into DNA - inhibits synthesis of DNA/RNA
Doxorubicin and Daunorubicin toxicity?
forms free radicals and oxygen radicals causing cardiac toxicity via membrane damage
Methotrexate MOA?
forms a polyglutamate adduct which is important for its duration of action

A folic acid antagonist which binds to DHF reductase
-- interferes w synthesis of thymidylate, purine nucleotides and the AA’s serine and methionine
-- inhibition of synthesis of DNA, RNA and proteins
Causes of development of resistance to methotrexate?
1. Decreased drug transport

2. altered DHFR

3. increased activity of DHFR

4. decreased polyglutamate formation
Major S/E of methotrexate?
bone marrow depression
CLINICAL: A patient tx w methotrexate develops bone marrow depression. How to tx?
“leucovorin rescue”

leucovorin (folinic acid) to reverse bone marrow depression. -- Normal cells can take up leucovorin, but tumor cells cannot
-- leucovorin rescues normal cells but not tumor cells
inhibition of DNA synthesis
-- 5-FU converted to FdUMP which inhibits thymidylate synthetase.
-- No dTMP formed, so no thymidine nucleotides formed
-- “thymidineless death”

Inhibition of RNA processing

No leukovorin rescue is possible
CLINICAL: Pt on chemo has cough w crackles, X-ray shows diffuse basilar infiltrates. What is the drug?
Bleomycin MOA?
(a peptide antibiotic)

-- fragmentation of DNA via formation of activated oxygen species (free radicals)
-- cells accumulate in G2 w chromatid breaks, gaps, fragments and translocations

Little BM toxicity
Drug w antiestrogenic effects for tx of breast cancer
What are the nitrosoureas?

Nitrosoureas MOA?
cross link DNA via alkylation; requires bioactivation
Nitrosoureas therapeutic action?
used to treat brain tumors (crosses BBB)
Which type of receptors must be present for the Tx of a breast cancer w/ GnRH analogs?
Estrogen receptors in the tumor tissue
Which drugs are the GnRH analogs?

MOA of GnRH analogs?
act on pituitary to inhibit the release of LH and FSH
-- decreased LH decreases estrogen synthesis by ovaries
Cisplatin MOA?
forms intra- and interstrand cross links at N7 of guanine via hydroylsis of chloride groups
-- inhibits DNA replication and transcription

Replacement of chloride with water forms the active drug
Cisplatin therapeutic use?
Treat testicular and lung carcinomas
Cisplatin S/E’s?
-- decreased by Cl diuresis
-- Cl stabilizes the platin complex

Renal toxicity causes loss of Mg, Ca, K and phosphate
Prednisone MOA?
apotosis in non-dividing cells
Prednisone therapeutic use?
chronic lymphocytic leukemia

Hodgkin’s lymphoma
Dose vs. Exposure time and tumor cell death
Radiation and alkylating agents ↑ tumor death by ↑ DOSE

Antimetabolites ↑ tumor death by ↑ EXPOSURE TIME, not by increasing dose
Major toxicity of alkylating agents?
moderate bone marrow depression

large doses cause
-- severe depression
-- leucopenia
-- thrombocytopenia
-- bleeding
Major toxicity of busulfan?
skin pigmentation

pulmonary fibrosis

adrenal insufficiency
Major toxicity of cyclophosphamide?
hemorrhagic cystitis
Major toxicity of cisplatin?
renal damage

acoustic nerve dysfunction
Major toxicity of procarbazine?
CNS depression
Major toxicity of glucorticoids = prednisone?

adrenal suppression

Major toxicity of cytarabine?
Major toxicity of 5-FU?
oral and GI ulceration
Major toxicity of 6-MP?
toxicity potentiated by allopurinol
Major toxicity of methotrexate?
oral and GI ulceration

bone marrow depression
Major toxicity of bleomycin?
pulmonary fibrosis
Major toxicity of dactinomycin?
bone marrow suppression
Major toxicity of doxorubicin?
cardiac toxicity

bone marrow depression

red urine (not hematuria)
Major toxicity of etoposide?
bone marrow depression
Major toxicity of vincristine?

peripheral neuritis

muscle weakness

paralytic ileus

Major toxicity of vinblastine?
loss of reflexes

bone marrow depression

Major toxicity of paclitaxel (taxol)?
bone marrow depression, peripheral neuropathy
Major toxicity of hydroxyurea?
bone marrow depression
Major toxicity of tamoxifen?
increased risk of endometrial cancer

menopausal symptoms
What is the S-phase-specific drug that inhibits DNA polymerase after metabolic activation?
cytarabine (cytosine arabinoside)
Cytarabine MOA?
(originally thought to inhibit DNA polymerase)

Inhibits DNA synthesis by inhibiting chain elongation when AraCTP is incorporated into the growing DNA chain
Cell cycle specific anti-tumor agents?
-- cytarabine
-- 5-FU
-- 6-MP
-- 6-TG

Paclitaxel (taxol)
Cell cycle NON-specific anti-tumor agents?
-- mechlorethamine
-- cyclophosphamide
-- chlorambucil
-- bisulfan
-- ciaplatin

Dacarbazine, Procarbazine
Nitrosoureas (carmustine, lomustine)
Daunorubicin, Doxorubicin
G1 phase
40% of cell cycle

Synth of cmpds needed to synth DNA
S Phase
40% of cell cycle

DNA replication and repair
Which drugs work in the S phase?

1. hydroxyurea – inhibits ribonucleotide reductase

2. 5-fluorouracil - inhibits thymidylate synthetase

3. 6-MP, 6-TP - inhibit purine synthesis

4. methotrexate - inhibits DHF reductase

5. cytarabine - inhibits DNA chain elongation
G2 phase
18% of cell cycle

Synth of molecules needed for mitosis
Which drugs work in the G2 phase?
1. bleomycin – fragmentation of DNA, cells accumulate in G2

2. etoposide -- stabilizes the bond between Topo II and DNA
-- Topo II is inhibited so double-stranded DNA breaks remain
-- DNA is degraded; blocks in late S-G2 (Topoisomerases cut 1- or 2-stranded DNA to allow the strand to unwind; TOP 1 and TOP 2 are necessary for DNA replication and RNA transcription; TOP 2 is needed for the completion of mitosis)
Which drugs work in the late G2, early M phase?
vincristine and vinblastine
-- bind to tubulin and prevent the assembly of microtubules
-- cells arrest in late G2 because mitotic filaments cannot form.

However, on the USMLE these vinca alkaloids act in the M phase
M Phase
2% of cell cycle

Which drugs work in the M phase?
1. paclitaxel (taxol)
-- enhances polymerization of tubulin
-- promotes microtubule assembly
-- stabilizes microtubules against depolymerization
-- causes mitotic arrest because anaphase cannot occur

2. vincristine and vinblastine (according to USMLE)
Non-phase specific drugs…?
1. can work at any step in the cell cycle, including Go

2. cells are more sensitive in late G1 and S because polynucleotides are more susceptible to alkylation in the unpaired state than in the helical form

3. toxicity usually expressed when cells enter S phase and progression through cell cycle is blocked

4. Example: doxorubicin - intercalates into DNA, DNA strand scission (single and double strand breaks) via effect on Topo II, (cells die in G2)