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Intro to path > 082914 antineoplastics part two > Flashcards

082914 antineoplastics part two Flashcards

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1
Q

alkylating agents mechanism

A

introduce alkyl groups into DNA, RNA, proteins (DNA is likely the most important target)

causes DNA crosslinks, strand breaks, misreading of code

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2
Q

cell cycle specificity of alkylating agents

A

can be:

cell cycle non specific (also affect G0 cells)–ex are mechlorethamine, carmustine

cell cycle specific phase nonspecific-ex are cyclophosphamide

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3
Q

what is unique of the alkylating agents?

A

least selective of the antineoplastics (tend to kill tumor and normal cells equally)

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4
Q

toxicities of alkylating agents

A

mechlorethamine-nausea and vomiting, myelosuppresion

carmustine-nausea and vomiting, delayed myelosuppression

cyclophosphamide-nausea and vomiting, limited myelosuppression, alopecia

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5
Q

what are the typical side effects of alkylating agents in general? (not for specific drugs)

A

hematopoeisis suppression (often used as indicator of therapeutic effectiveness and normal cell recovery)

GI effects (damage to intestinal mucosa…nausea and vomiting

alopecia

affect RAPIDLY DIVIDING tissues most

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6
Q

what two drugs are examples of nitrogen mustards in alkylating agents?

A

mechlorethamine

cyclophosphamide

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7
Q

what drug is an ex of nitrosoureas in alkylating agents?

A

carmustine

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8
Q

mechlorethamine cell cycle specificity

A

cell cycle nonspecific

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9
Q

what is mechlorethamine used for

A

in combo therapy for Hodgkin’s and non-Hodgkin’s LYMPHOMA

breast, lung, ovarian cancer

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10
Q

MOA of mechlorethamine

A 
bifunctional alkylating agent:
produces DNA cross links
highly reactive (disappears from blood in seconds to minutes)
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11
Q

what is the cell cycle specificity of cyclophosphamide

A

cycle specific phase nonspecific

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12
Q

what is unique about cyclophosphamide?

A

PRODRUG activated by liver cytochrome P450s

actual alkylating agent is phosphoramide mustard

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13
Q

toxicity of cyclophosphamide

A

bladder toxicity-sterile hemorrhagic cystitis (can be partially prevented with mesna)

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14
Q

what is good about cyclophosphamide?

A

very broad spectrum of activity, so used against wide variety of cancers

BREAST CANCER

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15
Q

cell cycle specificity of carmustine

A

cycle nonspecific

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16
Q

what is unique about carmustine?

A

crosses BBB very well

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17
Q

uses of carmustine

A

brain tumors, multiple myeloma, melanoma

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18
Q

when are antimetabolites most effective?

A

against tumors where cell proliferation is rapid

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19
Q

cell cycle specificity of antimetabolites

A

S phase specific

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20
Q

what are antimetabolites?

A

structural analogs of precursors of nucleic acid synthesis or other related pathways

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21
Q

MOA of methotrexate and what type of drug is it?

A

type: antimetabolite

MOA: binds to dihydrofolate reductase and prevents formation of tetrahydrofolate, which is needed for synthesis of dTMP

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22
Q

leucovorin rescue

A

high doeses of methotrexate are necessary to bind all dihydrofolate reductase

rescue host cells with leucovorin–leucovorin is folinic acid, which is a fully reduced folate that does not require to be reduced by DHFR (normal cells have increased ability to bring in leucovorin relative to tumor cells)

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23
Q

side effects of methotrexate

A

intestinal epithelium damage
bone marrow suppression
renal tubular necrosis
displaces other drugs from serum albumin

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24
Q

uses of methotrexate

A

acute lymphocytic leukemia
choriocarcinoma (methotrexate is #1 drug for this)
head neck breast lung
osteosarcoma

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25
fluorouracil: type of drug and MOA
antimetabolite pyrimidine analog that is activated in cells to FUTP which inhibits RNA synthesis. also activated to FdUMP which interferes with thymidylate synthase and ultimately DNA synthesis
26
side effects of fluorouracil
nausea, anorexia, diarrhea | myelosuppression
27
uses of fluorouracil
BROAD spectrum: COLON, BREAST, stomach, pancreas, ovary, head, neck, bladder (mostly GI) basal cell carcinoma
28
cytarabine: type of drug and MOA
antimetabolite pyrimidine (cytidine) analog that competes for phosphoyrlation of cytidine; competes for incorrporation into DNA and causes chain termination
29
side effects of cytarabine
``` marked myelosuppresion (limits dose) neurotoxic ```
30
uses of cytarabine
acute leukemias (acute myelocytic leukemia for ex)
31
mercaptopurine: type of drug and MOA
antimetabolite purine analog-converted in cells to ribonucleotide that inhibits RNA and DNA synthesis
32
sides effects of mercaptopurine
bone marrow depression vomiting, nausea, anorexia jaundice
33
uses of mercaptopurine
acute leukemias
34
TPMT is important for mercaptopurine b/c?
TPMT degrades mercaptopurine (6MP) to inactive form of 6 methyl MP. If person has non functional allele for it, has increased risk of serious bone marrow toxicity with normal dose if pt has two copies of nonfunctional TPMT, then can't tolerate the 6MP
35
hydroxyurea: type of drug and MOA
antimetabolite inhibits ribonucleotide reductase (blocks conversion of ribonucleotides to dNTPs, preventing DNA synthesis arrests cells then at G1-S point
36
major uses of hydroxyurea
granulocytic leukemia
37
side effects of hydroxyurea
hematopoietic depression | GI disturbances
38
examples of the vinca alkaloids, and what class of drug are the vinca alkaloids?
vincristine, vinblastine class: natural products
39
MOA of vinca alkaloids
binds to tubulin, inhibiting proper formation of microtubules and mitotic spindle arrests cells in metaphase
40
how are vincristine and vinblastine similar or different?
similar in that structurally related different in their toxicities and their antitumor spectrum
41
side effects of vinblastine
strongly myelosuppressive epithelial ulcerations
42
side effects of vincristine
significantly less bone marrow toxic. than vinblastine alopecia, neuromuscular abnormalities (peripheral neuropathy)
43
uses of vinblastine
lymphomas, breast cancer
44
uses of vincristine
acute lymphocytic leukemia lymphomas Wilm's tumor neuroblastoma
45
``` MOA of taxanes and what class are taxanes under? ```
class: natural products MOA: enhances assembly and stability of microtubules by binding to beta subunit of tubulin, blocks late in G2 phase (this phase is more sensitive to radiation so paclitaxel may be used as a radiosensitizer)
46
paclitaxel is an example of what type of drug? what class?
taxane, natural products
47
uses of paclitaxel
refractory ovarian cancer | breast cancer
48
sides effects of paclitaxel
dose limiting leukopenia peripheral neuropathy myalgia, arthralgia
49
doxorubicin: drug type/class?
antitumor antibiotic, natural products
50
cell cycle specificity of doxorubicin
cycle specific phase non specific
51
uses of doxorubicin
wide spectrum of activity lymphomas, breast, ovary most widely prescribed agent in its class
52
MOA of doxorubicin
intercalates in DNA, distorting the DNA helix binds to DNA and topoisomerase II causes lipid peroxidation and free radical generation
53
which drug has as a side effect CARDIOMYOPATHY?
doxorubicin
54
side effects of doxorubicin
cardiomyopathy bone marrow depression alopecia GI problems
55
bleomycin: class of drug
natural products
56
MOA of bleomycin
mix of IRON-containing glycoypeptides that bind to DNA causes oxidative-like damage to DNA which lead to DNA strand breaks
57
cell phase specificity of bleomycin
phase specific for G2
58
uses of bleomycin
germ cell tumors of testes and ovaries | head, neck, lung, lymphomas
59
side effects of bleomycin
minimal myelosuppression PULMONARY TOXICITY skin vesiculation, hyperpigmentation *lung and skin have lowest levels of bleomycin hydrolase for inactivating the drug
60
etoposide: class of drug
natural compounds
61
MOA of etoposide
irreversibly stabilizes DNA-topoisomerase II complexes (causing dsDNA breaks that can't be repaired)
62
cell cycle specificity of etoposide
late G2 phase
63
uses of etoposide
lymphomas, acute leukemia, small cell lung, testis
64
side effects of etoposide
``` leukopenia nausea vomiting diarrhea alopecia ```
65
biological response modifiers
naturally occurring proteins designed to mimic natural proteins limitation is that response can be variable,;serious side effects have happened
66
filgrastim
goal is to limit chemo-induced neutropenia promotes progenitors of neutrophils
67
side effect of filgrastim
bone pain
68
trastuzumab drug type and class
monoclonal antibodies, natural compounds
69
MOA of trastuzumab
humanized monoclonal antibody that binds to HER2 (human epidermal growth factor) receptor to block proliferation of cells; may illicit immune response against HER2+ cells
70
uses of trastuzumab
breast cancers that overexpress HER2, so is a target therapy
71
side effects of trastuzumab
cardiomyopathy-often reversible hypersensitivity infusion rxns-fever, chills
72
cisplatin: class of drug?
miscellaneous agents
73
MOA of cisplatin
platinum coordination complex-hydrolysis yields activated species which causes DNA crosslinks
74
cell cycle specificity of cisplatin
cycle specific phase non specific
75
uses of cisplatin
wide spectrum testicular cancer ovarian cancer
76
side effects of cisplatin
``` NEPHROTOXICITY ototoxicity peripheral neuropathy electroylyte distrubances nausea, vomiting mylosuppression ```
77
MOA of procarbazine
activated in vivo to a methylating agent which causes chromosomal damage an atypical alkylating agent
78
uses of procarbazine
Hodgkin's lymphoma
79
side effects of procarbazine
myelosuppression, nausea, vomiting
80
uses of hormone and hormone antagonist therapies against cancer
good for tumors that are steroid hormone dependent
81
possible strategies for hormone therapy against cancer
opposite steroidal compounds (estrogens for prostate cancer, etc) anti-hormonal compounds
82
benefits of hormonal therapy against cancer
responses to it can be dramatic and prolonged and has other beneficial side effects (not just for tumor)-ex is progestins as an appetite stimulant for cancer pts
83
prednisone MOA
binds to steroid receptors which act to modulate several aspects of cell growth (may arrest cells at G1; depress expression of many growth-related genes, induce nucleases which may modulate cell lysis)
84
what forms of antiestrogenic therapies are used to treat cancer?
estrogen receptor antagonists (tamoxifen, raloxifene) aromatase inhibitors (letrozole)
85
advantages of nonsteroidal aromatase inhibitors
oral, rapid onset estrogen below detectable levels no androgenic side effects
86
tamoxifen MOA
antiestrogen that compoetitively blocks estrogen receptors in breast tissue (estrogen agonist bone tissue)
87
cell cycle specificity of tamoxifen
cytostatic | tumor regrows when tamoxifen is removed
88
uses of tamoxifen
advanced post menopausal breast cancer premenopausal metastatic breast cancer breast cancer prophylaxis
89
what is tamoxifen activated by?
CYP2D6
90
side effects of tamoxifen and letrozole
nausea menopause like symptoms fatigue bone and other musculoskeletal pain
91
MOA of letrozole
blocks conversion of androgens to estrogens by inhibiting aromatase
92
uses of letrozole
1st line treatment of post menopausal locally advanced or metastatic breast cancer
93
what are some antiandrogenic approaches to prostate cancer?
``` GnRH analogs (leuprolide) non-steroidal androgen receptor blockers (flutamide) ```
94
leuprolide MOA
analog of GnRH (initially stimulates LH and FSH release causing testosterone surge, but after 2-4 weeks, it desensitizes GnRH signaling, decreasing LH/FSH and decreasing testosterone
95
uses of leprolide
advance hormonally response prostate cancer
96
side effects of leprolide
hot flashes | impotence
97
flutamide MOA
nonsteroidal antiandrogen that blocks androgen receptor
98
uses of flutamide
treatment of metastatic prostate cancer
99
side effects of flutamide
gynecomastia diarrhea hepatotoxicity
100
cell cycle specificies of all the antineoplastics
see part one lecture with three slides
101
major cause of chemotherapeutic failure
selection and overgrowth within tumor-resistance
102
what is a key strategy in overcoming resistance from tumor cells with chemotherapy?
combination therapy
103
how does multi-drug resistance occur?
mediated by ATP-dependent drug efflux pumps
104
principles of combination chemotherapy
different cell cycle specificites (to hit both those in and out of cell cycle) active as single agents non-overlapping toxicities different MOA
105
sequential blockade
simultaneous action of two inhibitors acting on different steps of linear metabolic pathway
106
concurrent inhibition
inhibitors block two sepearte pathways that lead to same end product
107
complementary inhibition
one drug affects fxn of an end product and the other drug affects the synthesis of that end product ex: cytarabine and doxorubicin
108
rescue
rescue the pt's normal cells from the cancer treatment examples: leucovorin (folinic acid) to rescue cells after high dose methotrexate autologous bone marrow or stem cel transplant
109
synchronization
synchronize cells so they are in one phase and then use drug specific for that phase ex: low doses of fluorouracil to block in S phase, then high dose of cytarabine to kill in S phase
110
recruitment
mobilize slowly proliferatin or non proliferating cells to more rapid proliferation-bring cells out of G0 and back into cell cycle and then hit them with cycle specific drugs

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