Therapeutic Agents For Cancer Flashcards
1
Q
diagnosis of cancer relies most heavily
A
invasive tissue biopsy
2
Q
3rd leading Tumor site under the age group 20-39 for in men and women
A
Male = colorectal Female = colorectal
3
Q
Give in ascending order the tumor sites under ages 40-59 in both males and females
A
Males = esophagus, pancreas, liver, colorectal, lungs
Female = pancrreas, ovary, colorectal, breast, lung
4
Q
Goal of cancer treatment is
A
first to eradicate the cancer.
5
Q
CANCER TREATMENTS Are divided into 2 main types:
A
Local treatments
Systemic treatments
6
Q
Local treatments include
A
surgery, radiation therapy (including photodynamic therapy), and ablative approaches, including radiofrequency and cryosurgical approaches.
7
Q
Systemic treatments include
A
chemotherapy (including hormonal therapy and molecularly targeted therapy) and biologic therapy (including immunotherapy
8
Q
Whar are Conventional “cytotoxic” chemotherapy agents
A
These agents mainly target DNA structure or segregation of DNA as chromosomes in mitosis.
9
Q
What are Targeted agents
A
Refer to small molecules or “biologics” designed and developed to interact with a defined molecular target important in maintaining the malignant state or expressed by the tumor cells.
10
Q
Hormonal therapies
A
Capitalize on the biochemical pathways underlying estrogen and androgen function and action as a therapeutic basis for approaching patients with tumors of breast, prostate, and uterus.
11
Q
Biologic therapies
A
Are often macromolecules that have a particular target or may have the capacity to induce a host immune response to kill tumor cells.
12
Q
Chemotherapy can be administered as an adjuvant, meaning?
A
attempts to eliminate clinically unapparent tumor that may have already disseminated
addition to surgery or radiation, even after all clinically apparent disease has been removed.
13
Q
Neoadjuvant chemotherapy refers to
A
administration of chemotherapy before any surgery or radiation to a local tumor in an effort to enhance the effect of the local treatment.
14
Q
G1 to S phase (CDK4/6 INHINITOR) includes
A
Palbociclib
Abemaciclib
Ribociclib
15
Q
S phase specific drugs
A
Cytosine arabinoside
Hydroxyurea
Irinotecan
Topotecan
16
Q
S phase specific self-limiting
A
6-mercaptopurine
Methotrexate
17
Q
M phase specific drugs
A
Vincristine
Vinblastinr
Packitaxel
18
Q
What are the six major types of alkylating agents are used in chemotherapy of neoplastic diseases
A
NANTED
Nitrogen mustards Alkyl sulfonates Nitrosoureas Triazenes Ethyleneimines DNA-methylating drugs, including procarbazine, temozolamide, and dacarbazine
19
Q
Chemotherapeutic alkylating agents have in common the property of
A
forming highly reactive carbonium ion intermediates
20
Q
Alkylating agents cause Cytotoxic effects are due to
A
Mispair with thymine residues
Creates lability in the imidazole ring
Cross-linking of two nucleic acid chains or the linking of a nucleic acid to a protein
21
Q
most widely used agent of this alkylating agents undergoes metabolic activation (hydroxylation) by CYP2B
A
Cyclophosphamide
22
Q
Alkylating agent activated in the liver by CYP3A4
Which Proceeds more slowly than activation of cyclophosphamide, with greater production of dechlorinated metabolites and chloroacetaldehyde
A
Ifosfamide
23
Q
Newest approved drug
this drug may derive from this purine-like structure; produces slowly repaired DNA cross-links, lacks cross-resistance with other classical alkylators, and has significant activity in chronic lymphocytic leukemia (CLL) and large-cell lymphomas
A
Bendamustine
24
Q
Transfers methyl groups rather than ethyl groups
Requires initial activation by hepatic CYPs through an Ndemethylation reaction.
In the target cell, spontaneous cleavage of the metabolite, metyhyl-triazeno-imidazolecarboxamide (MTIC), yields an alkylating moiety, a methyl diazonium ion.
A
Dacarbazine
25
Which include compounds such as
1,3-bis-(2-chloroethyl)-1nitrosourea (carmustine [BCNU]),
1-(2-chloroethyl)-3cyclohexyl-1-nitrosourea (lomustine [CCNU]), and its methyl derivative (semustine [methyl-CCNU]), as well as the
antibiotic streptozocin (streptozotocin)
Exert their cytotoxicity through the spontaneous breakdown to an alkylating intermediate, the 2-chloroethyl diazonium ion.
Nitrosoureas
26
Pharmacologic Actions of alkylating agents include
interfere with DNA integrity and function and to induce cell death
27
certain alkylating agents may have damaging effects on tissues with
normally low mitotic indices (e.g., liver, kidney, and mature lymphocytes); effects in these tissues usually are delayed.
28
Lethality of DNA alkylation depends on
recognition of the adduct, the creation of DNA strand breaks by repair enzymes, and an intact apoptotic response.
29
In nondividing cells, DNA damage activates a checkpoint that depends on the presence of
p53 gene
30
Malignant cells with mutant or absent p53 fail to suspend cellcycle progression undergo__________, and can exhibit resistance to __________
do not undergo apoptosis, and can exhibit resistance to alkylating drugs
31
Resistance to an alkylating agent develops rapidly when it is used as
single agent
32
Mechanisms of Resistance of Alkylating agents
Decreased permeation of actively transported drugs
Increased intracellular concentrations of nucleophilic substances
Increased activity of DNA repair pathways
Increased rates of metabolic degradation of the activated forms of cyclophosphamide and ifosfamide to their inactive keto and carboxy metabolites
Loss of ability to recognize adducts
Impaired apoptotic pathways, with overexpression of bcl-2
33
Toxicities produced by Alkylating agents
Bone Marrow Suppression
Immunosuppression
Mucosal Toxicity
Neurotoxicity
34
suppresses all blood elements, particularly stem cells, and may produce a prolonged and cumulative myelosuppression lasting months or even years. For this reason, it is used as a preparative regimen in allogenic bone marrow transplantation.
Busulfan
35
Cause delayed and prolonged suppression of both platelets and granulocytes, reaching a nadir 4–6 weeks after drug administration and reversing slowly thereafer.
Carmustine and other chloroethylnitrosoureas
36
has lesser effects on peripheral blood platelet counts than do the other agents
Cyclophosphamide
37
nadir of the peripheral blood granulocyte count at_____________ and recovery in _____________
6–10 days
14–21 days
38
alkylating agents are Reversible at usual doses but can cause _______________ with extended treatment.
opportunistic infections such as:
Pneumocystis jiroveci pneumonia
Fungal infections
Reactivation of hepatitis B
39
Alkylating agents are highly toxic to dividing mucosal cells and to hair follicles, leading to
oral mucosal ulceration, intestinal denudation, and alopecia.
40
Nausea and vomiting commonly follow administration of
nitrogen mustard or BCNU
41
most neurotoxic of the alkylating agents and may produce altered mental status, coma, generalized seizures, and cerebellar ataxia.
Ifosfamide
42
cause seizures; in addition, it accelerates the clearance of phenytoin, an antiseizure medication
High-dose busulfan
43
is well-absorbed orally and is activated to the 4-hydroxy intermediate
Cyclophosphamide
44
Cyclophosphamide appears to be saturable at concentrations of the parent compound greater than
150 μM.
45
4-Hydroxycyclophosphamide and its tautomer, aldophosphamide, travel in the circulation to tumor cells, where aldophosphamide cleaves spontaneously, generating stoichiometric amounts of
phosphoramide mustard and acrolein.
46
Phosphoramide mustard is responsible for ____________
While acrolein causes ___________________
antitumor effects
hemorrhagic cystitis
47
Cystitis can be reduced in intensity or prevented by the parenteral coadministration
mesna
48
Brisk hematuria in a patient receiving daily oral therapy should lead to immediate
drug discontinuation
49
Cyclophosphamide can be used in full doses in patients with
renal dysfunction because it is eliminated by hepatic metabolism.
50
Cyclophosphamide can be Can be administered Via
IV or PO
51
Maximal plasma concentrations of Cyclophosphamide are achieved about _____ after oral administration;
the t 1/2 of parent drug in plasma is about________.
1 h
| 7 h
52
an essential component of many effective drug combinations for non-Hodgkin lymphomas, other lymphoid malignancies, breast and ovarian cancers, and solid tumors in children.
Cyclophosphamide
53
Complete remissions and presumed cures have been reported when cyclophosphamide was given as a single agent for
Burkitt lymphoma
54
Cyclophosphamide is frequently is used in combination with________ and a_______ as adjuvant therapy after surgery for breast cancer
doxorubicin
taxane
55
Cyclophosphamide DOSAGE:
As a single agent
daily oral dose of 100 mg/m 2for 14 days has been recommended for patients with lymphomas and CLL
56
Cyclophosphamide DOSAGE:
in combination with other drugs in the treatment of breast cancer and lymphomas
Higher doses of 500 mg/m 2IV every 2-4 weeks
57
lower limit for dosage adjustments in prolonged therapy of cyclophosphamide
neutrophil nadir of 500-1000 cells/mm 3
58
In regimens associated with bone marrow or peripheral stem cell rescue, cyclophosphamide may be given in total doses of
5-7 g/m 2over a 3-5 day period
59
GI ulceration, cystitis (counteracted by mesna and diuresis) and less commonly, pulmonary, renal, hepatic, and cardiac toxicities (a hemorrhagic myocardial necrosis) may occur after high-dose therapy with high-dose therapy with total doses
>200 mg/kg
60
approved for treatment of patients with relapsed germ cell testicular cancer and is frequently used for first-time treatment of pediatric or adult patients with sarcomas.
Ifosfamide
61
It is a common component of highdose chemotherapy regimens with bone marrow or stem cell rescue
Ifosfamide
62
toxicity of ifosfamide is thought to result from a metabolite
chloroacetaldehyde
63
In nonmyeloablative regimens, ifosfamide is infused intravenously over at least ________ at a dose ___________
30 min at a dose of ≤ 1.2 g/m/d for 5 days
64
The parent compound, ifosfamide, has an elimination t1/2 in plasma of ___________ after doses ___________
~1.5 hours after doses of 3.8-5 g/m 2
65
have broad antineoplastic activity and have become the foundation for treatment of ovarian, head and neck, bladder, esophagus, lung, and colon cancers.
Platinum coordination complexes
66
Cisplatin, carboplatin, and oxaliplatin enter cells by
high-affinity Cu 2+transporter CTR1
67
After intravenous administration, cisplatin has an initial plasma elimination t 1/2of
25–50 min
68
More than_____ of the platinum cisplatin in the blood is covalently bound to plasma proteins.
90%
69
High concentrations of cisplatin are found in
kidney, liver, intestine, and teste
70
by 24 h, up to_____ is excreted, and by 5 days, up to ______of the administered cisplatin dose is recovered in the urine, mostly covalently bound to protein and peptides.
25%
43%
71
usual dosage of cisplatin in days, weeks, and month
20 mg/m/day 2for 5 days, 20-30 mg weekly for 3-4 weeks, or 100 mg/m 2 given once every 4 weeks.
72
appropriate amount of cisplatin then is diluted in a solution containing dextrose, saline, and mannitol and administered intravenously
over 4–6 h
73
inactivates cisplatin
aluminum
74
Toxicities of cisplatin
Cisplatin-induced nephrotoxicity
Ototoxicity is manifested by tinnitus and high-frequency hearing loss.
Progressive peripheral motor and sensory neuropathy (higher doses)
Mild-to-moderate myelosuppression
Electrolyte disturbances, including hypomagnesemia, hypocalcemia, hypokalemia, and hypophosphatemia, are common.
75
much less reactive than cisplatin, the majority of drug in plasma remains in its parent form, unbound to proteins.
Carboplatin
76
Most carboplatin is eliminated via renal excretion, with a t 1/2 in plasma of
~2 hours.
77
A small fraction of carboplatin binds irreversibly to plasma proteins and disappears slowly, with a t 1/2 of
≥ 5 days.
78
Carboplatin toxicities
Less nausea, neurotoxicity, ototoxicity, and nephrotoxicity than cisplatin
More Myelosuppression
hypersensitivity reaction
79
like cisplatin, has a very brief t 1/2in plasma, probably as a result of its rapid uptake by tissues and its reactivity.
Oxaliplatin
80
No dose adjustment for oxaliplatin is required for patients with a CrCl
≥20 ml/min
81
Oxaliplatin’s effectiveness in colorectal cancer is perhaps due to its
MMR- and HMG-independent effects.
82
Oxaliplatin in combination with 5-FU, it is approved for treatment of patients with
colorectal cancer.
83
an essential dietary factor that is converted by enzymatic reduction to a series of tetrahydrofolate (FH)4 cofactors that provide methyl groups for the synthesis of precursors of DNA (thymidylate and purines) and RNA (purines).
Folic acid
84
primary target of methorexate is
enzyme DHFR
85
toxic effects of methotrexate may be terminated by administering
leucovorin
86
dihydrofolic acid polyglutamates that accumulate in cells in behind the blocked DHFR reaction also acts as inhibitors
TS and other enzymes
87
Methotrexate is readily absorbed from the GI tract at doses of
<25mg/m
88
Approximately______ of methotrexate binds to plasma proteins.
50%
89
Methotrexate has been used in the treatment of_________
severe, disabling psoriasis
90
Methotrexate has been used in the treatment of severe, disabling psoriasis in doses of
2.5 mg orally for 5 days, followed by a rest period of at least 2 days, or 10-25 mg intravenously weekly.
91
Methotrexate is a critical drug in the management of
acute lymphoblastic anemia (ALL) in children.
92
primary toxicities of antifolates affect the bone marrow and the intestinal epithelium and correct within
10-14 days
93
_______ requires enzymatic conversion to the nucleotide status (ribosylation and phosphorylation) in order to exert its cytotoxic activity.
5-FU
94
________ inhibits TS and blocks the synthesis of TTP, a necessary constituent of DNA.
FdUMP
95
administered parenterally, because absorption after oral ingestion of the drug is unpredictable and incomplete
5-FU
96
5-FU Given by continuous intravenous infusion for
24-120 hours.
97
5-FU in combination with leucovorin and oxaliplatin or irinotecan in the adjuvant setting is associated with a survival advantage for patients with
colorectal cancers.
98
Cytarabine (1-ß-D-arabinofuranosylcytosine; Ara-C) is the most important antimetabolite used in the therapy
single most effective agent for induction of remission in this disease.
AML
99
Ara-C activates the transcription factor______ and stimulates the formation of________, a potent inducer of apoptosis.
AP-1
ceramide
100
after oral Ara-C administration, only ______ of the drug reaches the circulation
~20%
101
This drug must be given intravenously.
CYTARABINE
102
Half life of CYTARABINE
t ½of 10 minutes
103
Two dosage schedules are recommended for administration of cytarabine
Rapid intravenous infusion
Continuous intravenous
1. Rapid intravenous infusion of 100 mg/m 2every 12 hours for 5-7 days, or
2. Continuous intravenous infusion of 100-200 mg/m/day2 for 5-7 days.
104
A difluoro analog of deoxycytidine, has become an important drug for patients with metastatic pancreatic; non-squamous, non-small cell lung; ovarian; and bladder cancer.
GEMCITABINE
105
standard dosing schedule for gemcitabine (GEMZAR) is
30-minute IV infusion of 1-1.25 g/m 2on days 1, 8, and 15 of each 21- to 28-day cycle, depending on the indication.
106
principal toxicity of gemcitabine is
myelosuppression
107
are approved agents for human leukemias and function as analogs of the natural purines, hypoxanthine and guanine
6-Mercaptopurine (6-MP) and 6-Thioguanine (6-TG)
108
incorporated into DNA, where it induces strand breaks and base mispairing. Strand breaks depend on the presence of an intact MMR system, the absence of which leads to resistance.
6-Thioguanine
109
Absorption of mercaptopurine is incomplete (10-50%) after oral ingestion; the drug is subject to first-pass metabolism by___________ in the liver.
xanthine oxidase
110
Oral bioavailability is increased when mercaptopurine is combined with high-dose
methotrexate
111
principal toxicity of 6-MP is
bone marrow depression.
112
are cell-cycle-specific agents and, in common with other drugs such as colchicine, podophyllotoxin, the taxanes, and the epothilones, block cells mitosis
VINKA ALKALOIDS
113
biological activities of the vincas can be explained by their ability to bind specifically to ________ and to block its polymerization with a tubulin into microtubules
B tubulin
114
limited myelosuppressive action of__________ makes it a valuable component of several combination therapy regimens for leukemia and lymphoma,
vincristine
115
lack of severe neurotoxicity of____________ is a decided advantage in lymphomas and in combination with cisplatin against testicular cancer.
vinblastine
116
employed in treating bladder cancer, testicular carcinomas and Hodgkin’s disease.
Vinblastine
117
In patients with hepatic dysfunction (bilirubin >3 mg/dL), a ________reduction in dose of any the vinca alkaloids is advisable
50-75%
118
pharmacokinetics of each of the 3 drugs are similar, with an elimination
t 1/2 of ___ hours for vincristine,
____hours for vinblastine, and
____hours for vinorelbine.
20
23
24
119
given intravenously; special precautions must be taken against subcutaneous extravasation, because this may cause painful irritation and ulceration.
Vinblastine sulfate (VELBAN, others)
120
In regimens designed to cure testicular cancer, vinblastine is used in doses of
0.3 mg/kg every 3 weeks.
121
After a single dose of 0.3mg/kg of body weight of vinblastine myelosuppression reaches its maximum in
7-10 days.
122
Doses of vinblastine should not be reduced by 50% for patient with plasma bilirubin level of
>1.5mg/dL.
123
nadir of the leukopenia that follows the administration of vinblastine usually occurs within______ days, after which recovery ensues within____ days.
7-10
7
124
used together with glucocorticoids is the treatment of choice to induce remissions in childhood leukemia and in combination with alkylating agents and anthracycline for pediatric sarcomas
Vincristine sulfate
125
the common intravenous dosage for vincristine is
2 mg/m 2 of body surface area at weekly or longer intervals.
126
clinically toxicity of vincristine is mostly
neurological, early sensory changes do not warrant dose reduction.
127
________ occurs in ~20% of patients given vincristine is is reversible
Alopecia
128
This drug has a unique ability to promote microtubule formation at cold temperature and in the absence of GTP
PACLITAXEL
129
Paclitaxel is administered as 3-hour infusion of
or as a weekly 1-hour infusion of
135-175 mg/m 2every 3 weeks
80-100 mg/m.
130
Paclitaxel exerts its primary toxic effects on
bone marrow.
131
Paclitaxel exerts its primary toxic effects on bone marrow.
Neutropenia usually occurs ______
and reverses rapidly by days ______
8-11 days after
And days 15-21.
132
have a tetracyclic ring structure attached to an unusual sugar, daunosamine.
ANTHRACYCLINES
133
ANTHRACYCLINES can intercalate with DNA, directly affecting
transcription and replication.
134
ANTHRACYCLINES has the ability to form a tripartite complex with
topoisomerase II and DNA.
135
recommended dose of Doxorubicin is __________
Administered as a single rapid intravenous infusion that is excreted after_____ days.
60-75 mg/m2
21
136
Doxorubucin is effective in malignant
lymphomas
137
most important long-term toxicity of doxorubicin
Cardiomyopathy
138
What is the major dose-limiting complication of doxorubicin, with leukopenia usually reaching a nadir during the_______ week of therapy and recovering by the________ week
Myelosuppression
second
fourth
139
What do you call the Erythematous streaking near the site of infusion by allergic reaction with doxorubicin
ADRIAMYCIN flare
140
Cells in the S and G 2phases of the cell cycle are most sensitive to
etoposide and teniposide.
141
intravenous dose of etoposide (VEPESID, others) for testicular cancer in combination therapy is_____________, or ___________on alternate days for three doses
50-100 mg/m 2 for 5 days
100 mg/m 2
142
When given intravenously, etoposide should be administered slowly over a _______minute period to avoid hypotension and bronchospasm
30- to 60
143
disturbing complication of etoposide therapy has emerged in long-term follow-up of patients with childhood acute lymphoblastic leukemia, who develop an unusual form of acute nonlymphocytic leukemia with a translocation in chromosome
11q23
144
dose-limiting toxicity of etoposide is leukopenia, with a nadir at ______ and recovery by ____ weeks.
10-14 days
3
145
unique group of DNA-cleaving antibiotics.
BLEOMYCIN
146
BLEOMYCIN is Administered IV, IM, or SC, or instilled into for local treatment of
bladder cancer.
147
BLEOMYCIN have Elimination half time:
~3hrs
148
About ____ of bleomycin is excreted intact in urine
⅔
149
After IV administration of bolus dose of 15 mg/m2, peak concentrations of bleomycin of about ______ are achieved in plasma.
1-5 mg/mL
150
Decreased doses of bleomycin if CrCl
<60 mL/min
151
Recommended dose of bleomycin is _______ given weekly or twice weekly by IV, IM, or SC.
10-20 units/m 2
152
BLEOMYCIN is Highly effective against germ cell tumors of
testis and ovary.
153
Bleomycin causes constellation of cutaneous toxicities, these are
Hyperpigmentation
Hyperkeratosis
Erythema
Ulceration
154
Most serious adverse reaction of bleomycin
Pulmonary Toxicity
155
Other toxic reactions of bleomycin
Hyperthermia, Headache, Nausea and Vomiting, Peculiar acute fulminant reaction observed in patients with lymphomas.
