Anti-Neoplastic Agents III
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Name the two major groups of compounds that disrupt cell
division by targeting tubulin. In
general, how do the two groups differ?
- alkaloids & Taxanes; Vinca alkaloids bind to β-tubulin and prevents polymerization w/α-tubulin and formation of microtubules while
bind and cause aggregation.
Of the four active dimeric alkaloids, which two have been
used clinically for a number of leukemias, lymphomas and testicular cancer.
Vinblastine & vincristine
____________________ is able to dissolve microtubules.
In vinca alkaloids, cell division is arrested in which
What happens to the cells after vinca alkaloids bind β-tubulin?
What is the potential problem of this?
- Cells undergo an apoptotic-like process in which the
- duplicated chromosomes disperse throughout the cytosol in clumps. Potential problems occur because neurons have
- large amounts of microtubules for transport.
_______________ results in increased levels of the efflux
protein P-glycoprotein in vinca alkaloid resistance. This can be overcome by _________________.
Gene amplification; calcium channel blockers
What can mutations in β-tubulin lead to with vinca alkaloids?
- Decreased binding of the vinca alkaloids to β-tubulin
- (reduces effectiveness)
List the primary toxicities associated with vinca alkaloids.
- Myelosuppression, neurological toxicity (loss of DTRs,
- numbness and tingling in extremities), rarely vocal cord paralysis &
- extraocular muscle function
What are the vinca alkaloids a standard component of
Pediatric leukemias, lymphomas, and solid tumors
What is the CHOP regimen used for?
- doxorubicin, prednisone) – very effective against large cell non-Hodgkins
Name the solid tumors of childhood vincristine is used for.
Wilms tumor, neuroblastoma, rhabdomyosarcoma
Which vinca alkaloid is more effective against adult
testicular cancer, bladder cancer and Hodgkins disease?
_______________ is active against non-small cell lung cancer
and breast cancer.
IV infusions of vinblastine can cause what serious injury?
Vinblastine used to be used with belomycin and cisplatin for
testicular cancer, but now _________ is used.
What is vinblastine active against?
- Component of standard ABVD (decarbazine, vinblastine,
- doxorubicin & belomycin) regimen for Hodgkin disease. Active against adult Kaposi sarcoma,
- neuroblastoma & histiocytosis X.
Vincrisinte can be used with ____________ for remission of
Adults are more prone to which severe toxicity with
vincristine compared to children?
_____________ formulation of vincristine is used in large-cell
lymphoma which produces less neurotoxicity.
Vincrisitine can produce both _________ _________(2) and
_________, both of which are reversible.
Severe constipation; alopecia
Do taxanes bind to the same or different site as the vinca
Name a synthetic version of paclitaxel.
Paclitaxel is administered in 50% EtOH and 50%
polyehtoxylated castor oil because it has _____ ________(2). In doing so, this enhances the potential for
Poor solubility; hypersensitivity reactions
In order to avoid hypersensitivity reactions with paclitaxel
administered in 50% EtOH and 50% polyethoxylated castor oil, what are patients
- H1 receptor & H2 receptor antagonists and a
How do taxanes arrest mitosis?
- By forming aberrant microtubular structures due to excessive
What drugs can inhibit the effectiveness of taxols?
- Drugs that inhibit cell-cycle progression prior to
- microtubule formation.
What are patient given to overcome bone marrow suppression
caused by paclitaxel?
Why does docetaxel produce greater neutropenia and fluid
Excess ADH release
Taxanes undergo extensive metabolism by ________ w/ some ________,
so little parent excreted.
_____________ is used w/estramustine for treatment of
hormone-refractory prostate cancer.
_______ are central drugs for treatment of metastatic
breast, ovarian, lung and head & neck cancers.
___________ more leukopenia & peripheral edema; while ______________
more hypersensitivity, muscle ache and neuropathy.
Camptothecin analogs target
_____________________ ___ a nuclear enzyme that relieve torsional stress
in supercoiled DNA.
Anthacycline drugs target _________________.
Topoisomerase I binds to DNA and makes a _____________ ________ (2) break via
a reversible transesterification rxn such that an enzyme tyrosine becomes
covalently bound to a 3’-phosphate of the DNA.
In addition to making a single strand break, topo-I does
Reseals the DNA
____________ bind and stabilize the DNA-topo-I complex. This results in
single-strand breaks that are not resealed.
Single strand breaks caused by camptothecin analogs leads to
__________ _________ breaks during replication.
Camptothecin analogs require cells to be cycling through
what cell phase to be sensitive to them?
Extensive double strand break formation may induce
Increased expression of topo-I could produce resistance or
decreased expression due to __________ __________ (2)
Mutations to topo-I to reduce camptothecin binding have been
shown _______ _________(2).
analog is indicated for treatment of previously treated ovarian and small cell
_____________ is indicated for advanced colorectal cancer
either w/5-FU (no prior failure) or without (prior 5-FU failure).
What is the dose-limiting toxicity of topotecan?
- Neutropenia w/or without thrombocytopenia (mucositis &
- diarrhea may become dose limiting)
What is irinotecan’s primary dose-limiting toxicity?
Delayed diarrhea (myelosuppresion is second most common)
List several classes of antibiotics and bacterial
fermentation products shown to have antitumor activity.
- Actinomycin D, Daunorubicin and analogs, Mitoxantrone,
- Bleomycins, Mitomycin
___________ ____ (2) has activity against solid tumors of
children and choriocarcinoma.
Actinomycin D is a __________________ that produces
What does the actinomycin molecule intercalate between which
blocks transcription of RNA?
Adjacent G-C base pairs
_____ dependent ____ polymerases more sensitive compared to _____
dependent ______ polymerases.
True/False Actinomycin D is a very potent inhibitor of
False; very potent inhibitor of rapidly diving cells.
Two important side effects of actinomycin are ________ and
__________ _________ (2).
Alopecia; extravasation injury
List indications for Actinomycin D.
- Childhood Wilm’s tumor where potentially curative
- (extensively), active against Kaposi’s sarcom, Ewing’s tumor and soft tissue
Patients on Actinomycin D may experience bone marrow
suppression with ___________.
Anthracycline antibiotics are Significant antitumor drugs
derived from the fungus __________________ _________ ____ ______
- peucetius var. caesius
Anthracycline antibiotics form a tripartite complex with
__________________ ___ & ____.
Topoisomerase II; DNA
Topo-II produces ___________ ____________ breaks to relieve
torsional stress on the DNA.
Formation of the tripartite complex prevents __________ and
produces multiple double-strand breaks.
_______________________ can produce can produce semiquinone
free radicals that can produce several reactive oxygen species.
What leads to anthracycline antibiotics’ major toxicity of
Production of reactive oxygen species
List the multiple resistance mechanisms seen in
P-glycoprotein and MRP induction
↑ glutathione peroxidase activity
↓ topo-II activity
- ↑ double strand repair capability (error-prone can still
- end up with apoptotic cell)
All anthracyclines need to be converted to what for
Idarubicin replaced ___________ for treatment of AML
generally in combination w/Ara-C.
__________ is active against malignant lymphomas, but also
solid tumors including breast.
What is the major dose-limiting toxicity for anthracyclines?
- Myelosuppression w/leukopenia followed by thrombocytopenia
- and anemia.
Name three side effects that are common in anthracycline
Stomatitis, GI distress and alopecia
Cardiomyopahty is a serious long-term toxicity for
anthracycline antibiotics. List the acute
and chronic effects.
- Acute: ST and T-wave changes can occur but these are
- Chronic: cumulative dose-related toxicity can produce a CHF
- that is not responsive to digitalis. Mortality approaches 50%. Risk increases
- to >20% of patients w/ total doses greater than 550 mg/m2
___________ is used for AML has less ability to produce
quinone-type free radicals and has less cardiotoxicity, but similar other
Bleomycins are antibiotics purified from _________________
___________ (2) fermentation products
Bleomycins A2 and B2 are what kind of
Copper chelating peptides
What are belomycins active against?
- Squamous carcinoma of the cervix; lymphomas & testicular
Belomycins are minimally _______ and _______________________
so can be combined w/other agents without potentiating these toxicities
Bleomycin causes oxidative damage to the ________________ of
___________ and other nucleotides.
The oxidative damage from belomycin leads to single &
double-strand breaks with cells accumulating at which phase of the cell cycle?
During belomycin treatment cells can show chromosomal
aberrations w/ ________ _______ (2), _______________ and translocations.
Chromatid breaks; fragmentation
Bleomycin can cause DNA damage involving ______ and ________
in which the metal-drug complex acts as a ______________ _____________.
O2; Fe++; ferrous oxidase
Why is toxicity of bleomycin see in the skin and lungs?
- It is degraded by a cellular hydrolase present in the liver,
- but not in the skin or lungs.
Bleomycin is effective against ____________ _______ tumors
of the testes and ovaries.
In combination with cisplatin, bleomycin is curative for
which type of cancer?
Used in the ABVD regimen for __________ ___________ (2) and
given intrapleurally for _________ __________ _________(3).
Hodgkin’s disease; malignant pleural effusions
Bleomycin can be instilled into the bladder to treat
The major dose-limiting toxicity for bleomycin is what?
Toxicity to the skin and lung
What 4 things can dermal toxicity from bleomycin include?
Hyperpigmentation, hyperkeratosis, erythema and ulceration
What is the most serious toxicity for bleomycin?
Pulmonary (particularly fibrosis)
What is the possible mechanism for pulmonary toxicity in
Increased expression of TGF-β by resident cells
Two derivatives of ______________ show significant
anti-tumor activity against pediatric leukemias, small cell carcinoma of the
lung, testicular tumors, Hodgkin’s disease and large cell lymphomas
Epipodophyllotoxins share the same mechanism of action as
which other types of drugs?
With epipodophyllotoxins, one sees accumulation of cells in
which of the cell phases?
S & G2 phases
What are the resistance mechanisms of epipodophyllotoxins?
- ↑ expression of mdr-1 (P-glycoprotein), Mutation or ↓
- expression of topo-II and Mutation of p53
The dose-limiting toxicity of epipodophyllotoxins is what?
Leukopenia (w/less thrombocytopenia)
What are the two common side effects seen with
GI distress and alopecia
What toxicity is seen with higher doses of
Hepatic (and hypersensitivity reactions)
What side effect can be seen when using etoposide for small
cell lung carcinoma and what is it due to?
Bronchospasm due to additives
Childhood acute lymphoblastic leukemia may develop an acute
nonlymphocytic leukemia w/ a translocation on chromosome _______ where a gene
that regulates _______________ ______ _____ ________ (4) found.
11; pluripotent stem cell proliferation
Teniposide is used to treat refractory _________ in
Is penetration into the CSF great with tenisposide?
What are the major toxicities of teniposide?
What is the standard agent for treating lymphocytic leukemia?
Some lymphoid malignancies cannot synthesis ____________ for
What does administration of L-asparaginase do?
- Converts plasma L-asparagine into L-aspartic acid and
- ammonia depriving cells of substrate.
Resistance of L-asparaginase includes expression of _______
___________ in the tumor cells.
How can hypersensitivity reactions be reduced with
- Use a pegylated enzyme preparation that has 5000 Da
- monomethyl polyethylene glycol conjugated to the enzyme.
___________ ________________ can produce a hypersensitivity
reaction, but not all.
With use of L-Asparaginase, several clotting factors can
become deficient leading to _________ ________________ (2).
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