Cancer Pharm (Kruse) Flashcards
Compare and Contrast oncogenes and tumor supressors
Oncogenes are genes that positively influence tumor formation (ras)
Tumor supressors are genes that negatively impact tumor growth (p53)
Some cancers affect the cell cycle. Discuss
proteins or pathways involved in regulating the checkpoints between the phases of the cell cycle may be absent or mutated which can lead to uncontrolled and unregulated cell cycle proliferation
Certain drugs will target the cell cycle to help reduce this proliferation (cell-cycle specific)
Activation of oncogenes overrides what part of the cell cycle?
Inactivation of tumor suppressor genes overrides what part of the cell cycle?
overrides G1 arrest
Overrides G2 arrest
Now the cell isn’t arrested when it should be, and can cause cancer
What is primary chemotherapy?
chemotherapy that is given as the primary treatment
used for advanced cancers with no other alt. tx or advanced metastatic disease
What is the goal of primary chemotherapy?
relieve tumor related symptoms
improve quality of life
prolong time to tumor progession
In what cancers or patients can primary chemotherapy be curative?
HL and NHL, choriocarcinoma, germ cell cancer, and AML
Burkitt’s lymphoma, Wilm’s tumor, Embryonal rhabdomyosarcoma, ALL
What is neoadjuvant chemotherapy
chemo that is given for a localized cancer in which alternative therapies exist but are less than completely affective
What is the goal of neoadjuvant therapy?
reduce the size of the tumor to make surgery easier/spare normal organs
typically given after surgery as well (becomes adjuvant therapy at that point)
What is adjuvant chemotherapy?
chemo used as an adjuvant (or help) to local therapy and administered after surgery has been preformed
What is the goal of adjuvant therapy?
reduce the incidence of local and systemic recurrence
improve the overall survival
effective at prolonging dz-free state and survival
What is growth fraction?
ratio of cell proliferation to G0 cells
this is the major determinant of a cancer’s responsiveness to chemotherapy
antineoplastics will be more effective on cells with a high growth fraction and will impact noncancerous high growth cells
What are normal body cells with high growth fraction?
cells of the bone marrow, GI, hair, sperm forming cells
Solid tumors can be difficult to treat because of what rule?
the growth fraction
the initial rate of growth is fast, but decreases overtime, such that by the time it is detected, it is no longer proliferating as rapidly, thus certain drugs won’t be as effective
Ex: burkitt’s lymphoma with high growth fraction, easier to cure with chemo, vs. colorectal carcinoma with a low growth fraction, chemo has a minor effect
Note, surgery/rad increase growth fraction which can increase chemo efficacy!
What is the log cell kill hypothesis?
antineoplastic therapy follows first-order kinetics: a given dose of drug destroys a constant fraction of cells
log cell kill hypothesis states that antineoplastic agents kill a fraction of cells rather than an absolute number per dose
therefore, only a limited log cell kill can be expected with each individual treatment
Why are antineoplastic agents delivered in a staggered/intermittent schedule?
high dose intermittent therapy allows recovery of normal, healthy tissues
agents given as constant infusions can include those that are rapidly metabolized or excreted as well as those that are cell cycle specific
What are some various routes of administration?
What are pharmacologic sanctuaries?
IV, PO
intracavity, intrathetcal, intraventricular, intraarterial, topical, isolated limb
implantable wafers
pharmacologic sanctuaries are regions where tumor cells are hard to reach (CNS)
What is combination chemotherapy?
it is the use of multiple agents, more successful than single agent regimens
- provides max cell killing within tolerated toxicity
- effective against broader range of cell lines with heterogenous population
- may delay or prevent drug resistant tumors
What are the 5 principles used in the design of combination chemotherapy regimens?
- each drug should have some individual therapeutic activity
- drugs that act by diff. mechanisms should net an increased log cell kill and decrease drug resistance
- drugs with different dose-limiting toxicities should be used in combination to avoid organ damage
- intensive intermittent treatment schedules should allow time for recovery in between
- several cycles of treatment should be given (6-8)
What are two primary(inherent) chemotherapy resistances?
drug resistance in the absence of prior exposure to available drugs
genomic instability of the cancer like p53 mutations
What are acquired chemotherapeutic drug resistances?
What are some examples?
develops after exposure to a cancer drug
gene amplification or supression
Examples:
decreased drug transport into the cell
reduced affinity of target
increased expression of enzyme that causes inactivation
increased expression of DNA repair enzymes
It is worth noting that exposure to chemo drugs can increase what?
increase the cancer heterogeneity, causing it to become less monoclonal and more difficult to treat and can become resistant to treatment
What is important about p-Glycoprotein?
To what kind of antineoplastics is there a high resistance to?
PGP expression is found in tissues with barrier functions (kidney, liver, GI) and BBB/PBB
a high baseline expression of PGP correlates with high primary resistance to natural products
if PGP is overexpressed, can lead to acquired drug resistance
What are common antineoplastic drug toxicities
death of rapidly proliferating normal cells
bone marrow
GI tract
hair follicles
oral mucosa
sperm forming cells
(many of these drugs can damage so much that they cause cancer later in life-alkylating agents)
Common adverse effects of antineoplastics?
N/V
fatigue
stomatitis
alopecia
myelosupression (dif. wound healing, increased infections)
low sperm count/azospermia
depressed development in children
How to minimize adverse effects of antineoplastics?
choose the route of administration with as little systemic toxicity
use of other pharm agents to decrease adverse effects (hemopoeitic agents, Zofran, bisphosphonates)
rest and recovery between doses
What are the five major types of alkylating agents?
- cyclophsphamide (N mustard)
- carmustine (Nitrosoureas)
- busulfan (alkyl sulfonates)
- procarbazine (methylhydrazine)
- dacarbazine (triazines)
also included is cisplatin, a platinum compound
What is the most widely used alkylating agent?
Cyclophsphamide
(most vomiting, too)
Alkylating agents are cell cycle (specific or nonspecific)?
Nonspecific!
What is the MOA of alkylating agents?
alkylating agents form covalent links between DNA of between guanine which prevents unwinding of the DNA (and thus prevents replication)
How is cyclophosphamide activated?
What are two cytotoxic products?
Which one causes hemorrhagic cystitis?
How is it treated?
Must past through CYP2B and hepatic cytochrome oxidase and hepatic aldehyde oxidase to become phosphoramide mustard (cytotoxic) and acrolein (cytotoxic)
Acrolein causes hem. cystitis
Mesna inactivates acrolein and is used prophylactically
What are the pharmacological adverse effects of alkylating agents?
acute toxicity is seen within 30-60 minutes, including nasuea and vomiting and tissue damage at injection site (can do oral instead, pretreat with Zofran)
Delayed toxicites include bone marrow depression, alopecia, nephrotoxicity, mucosal uleration, GI changes
What are some specific adverse effects of the following:
Cyclophosphamide
cisplatin
busulfan
hemorrhagic cystitis
renal tubular damage, ototoxicity
pulm. fibrosis
What are antimetabolites and are they cell cycle (specific or nonspecific)?
they are structural analogs to compounds necessary for cell proliferation
they block pathways that are involved in cell replication
they are cell cycle specific
What are the main categories of antimetabolites>
- folic acid analogs (methotrexate)
- pyrimidine analogs (5-fluorouracil)
- purine analogs (6-mercaptopurine)
How does methotrexate work?
What is used in addition to avoid systemic cell toxicity?
inhibits dihydrofolate reductase and is useful for cancer, RA and psoriasis
Used in conjunction with reduced rolate leucovorin to rescue normal cells
What drug is a pyrimidine structural analog?
How does the active compound work?
Fluorouracil
FdUMP covalently binds thymidylate synthase and blocks de novo synthesis of thymidylate
FdUTP and FUTP are incorporated into DNA and RNA to interfere with synthesis, function, processing and translation
Which drug is a purine structural analog?
how is it metabolized?
Does it undergo first pass metabolism?
mercaptopurine
metabolized by HGPRT
Yes, if taken orally and then is inactivated by xanthine oxidase
What is given along with 6MP (mercaptopurine) to prevent hyperuricemia due to tumor cell lysis?
If both allopurinol and PO 6MP are given together, what happens?
Allppurinol, a xanthine oxidase inhibitor
increased levels of 6MP and increased toxicity (fix by giving 50-75% less 6MP oral, or just give IV)
What is the cell cycle specific target of antimetabolites?
After the initial dose, is there any acute toxicity? What about adverse side effects?
S phase
Relatively little acute toxicity; diarrhea, myelosupression, N/V, immunosupression, thrombocytopenia, leukopenia, hepatotoxicty
What is the MOA for the Vinca alkaloids (vinblastine and vincristine)
Is it cell-cycle specific or nonspecific?
bind to B-tubulin and inhibit microtibile assembly (depolarization)
Cell cycle specific for the M phase (inhibits mitosis)
What are some common adverse effects of vinblastine and vincristine?
alopecia and bone marrow depression
vinblastine can cause myelosuppresion to a greater extent than vincristine
vincristine can cause neuro toxicities
What is the MOA for taxanes?
Are they cell cycle specific?
binds to B tubulin and stabilizes microtubule formation (so that they don’t work right)
Yes, for the M phase
What are some adverse effects of Paclitaxel and docetaxel (both taxanes-for breast cancer)?
Paclitaxel can cause hypersensitivity reactions in hands, toes, and taste changes
Docetaxel is taken into cells and retained longer and better, leading to smaller dosing and fewer side effects, but can cause hypersensitivity, neutropenia, and alopecia
What is the MOA for topoisomerase inhibitors?
What are the two classes?
Are they cell cycle specific?
Inhibiting topoisomerases leads to DNA damage and cell death
Camptothecins (topotecan, irinotecan) inhibit Topoisomerase I
Epipodophyllotocins (etoposide, teniposide) and anthracyclin antibiotics (doxorubicin and daunorubicin) inhibit toposiomerase II
Yes, at S mostly and G1/G2
What are the five antitumor antibiotic classes?
What is their main effect?
anthracyclines
dactinomycin
bleomycin
mitomycin
they effect the DNA
How do the anthracyclines work?
(Mainly Doxorubicin)
Is it cell cycle specific?
What kind of toxicity can occur?
Inhibits topoisomerase II, DNA intercalation
Not cell cycle specific
Can produce free radicals and cause cardiotoxicity, dysrhythmias and heart failure
How does Bleomycin work?
What kind of adverse effects does it have?
Causes single and double stranded DNA breaks
can cause pulmonary toxicity and usually presents as pneumonitis with cough, dyspnea, crackles, but with minimal myelosuppression so good in combination
How does Dactinomycin work?
Intercalation of DNA
How does asparaginase work?
Is it cell specific?
What are the acute side effects?
What are delayed side effects/toxicities?
hydrolyzes circulating L-asparagine into aspartic acid and ammonia, effectively inhibiting protein synthesis
Yes, for G1
hypersensitivity reaction (fever, chills, n/v, urticaria)
increased risk of clotting, bleeding, pancreatitis, CNS toxicity
What cancer is asparginase used for often?
ALL as a targeted therapy because they lack the enzyme aspariginase synthase
How are differentiating agents used for cancer (Tretinoin)?
used for acute promyelocytic leukemia as it binds to the PML-RARa fusion protein and antagonizes the inhibitory effect on the transcription of target genes
the neoplastic cells differentate into neutrophils which rapidly die
very successful treatment
can cause vit. A toxicity and retinoic acid syndrome
How can tyrosine kinases cause cancer?
When they are mutated, overexpressed or altered, tyrosine kinases can become oncoproteins
this can occur in the RTK or the cytoplasmic kinases
good news: good target for cancer therapy
How can Imatinib treat Chronic myelogenous leukemia?
Imatinib is a small molecule inhibitor of the ABL tyrosine kinase and can target the BCR-ABL fusion protein that results from the t(9;22) translocation in pts with CML
can also inhibit RTKs PDGFR and KIT
How do Erlotinib and gefitinib work?
what does it treat?
produces what side effects?
inhibit tyrosine kinase of the EFGR
refractory non-small cell lung cancer, pancreatic cancer
dermatologic toxicities
What is the MOA for tyrosine kinase and growth factor receptor inhibitors?
inhibit growth factor receptor signaling
inhibit tyrosine kinase activity
What is the mechanism of resistance of tyrosine kinase and growth factor receptor inhibitors?
What are common adverse effects?
point mutations in drug binding site can cause resistance
nausea, vomiting, acneform skin rash and hypersensitivity
What are biologic response modifiers?
agents that act indirectly to mediate their antitumor effects by enhancing the immunologic response to neoplastic cells
Includes: interferons and interleukin-2
How do interferons work?
What are the side effects?
inhibit cell growth, alter differentiation, interfere with oncogenes, alter surface antigens, increase phagocytic activity of macrophages, and augments cytotoxicity of lymphocytes for target cells
bone marrow depression, neutropenia, anemia, renal toxicity, edema, arrhythmias
How does interleukin-2 work?
What is the major toxicity?
increases cytotoxicity killing by T cells and NK cells
capillary leak syndrome
What is one of the cool things about using antibodies to treat cancer?
Antibodies can target spcific antigens on specific cancers
example: Rituximab-CD20 in non hodgkin’s lymphoma
What are some treatments for malignant melanoma?
Dacarbazine and cisplatin (low response rate)
biologic agents like IFNa and IL2 (better response)
Nivolumab and pembrolizumab (if unresectable or metastatic as monotherapy)
What is a common mutation in malignant melanoma?
What treatments are good treatment for this mutation?
BRAF V600E mutation present in a large majority of melanomas
constitutive activation of BRAF kinase
vemurafenib, dabrafenib, encorafenib target BRAF directly
Common toxicities
Methotrexate, melphalan-mucositis
bleomucin, busulfan-pulmonary fibrosis
vincristine-peripheral neuropathy
cisplatin-ototoxicity
doxorubicin, daunorubicin-cardiotoxicity
cisplatin, cyclophosphamide-nephrotoxicty
cyclophphamide, ifosfamide-hemorrhagic cystits
