Cancer Pharmacology Flashcards
Categories of alkylating agents used in chemotherapy
Bis (chloroethyl) amines, nitrosoureas, aziridines, alkylsulfonate, non-classic alkylating agents, platinum analogs
Of the alkylating agents, name the 4 bis (chloroethyl) amines
Cyclophosphamide
Mechlorethamine
Melphalan
Chlorambucil
Of the alkylating agents, name the 2 nitrosureas
Carmustine
Streptozocin
Of the alkylating agents, what is the major aziridine used in chemotherapy?
Thiotepa
Of the alkylating agents, what is the major alkylsulfonate used in chemotherapy?
Busulfan
3 non-classic alkylating agents
Procarbazine
Dacarbazine
Bendamustine
Of the alkylating agents, name the 3 platinum analogs
Cisplatin
Carboplatin
Oxaliplatin
4 categories of antimetabolites used in chemotherapy
Antifolates
Fluoropyrimidines
Deoxycytidine analogs
Purine antagonists
Of the antimetabolites, what are the 3 antifolates used in chemotherapy?
Methotrexate
Premetrexed
Pralatrexate
Of the antimetabolites, what are the 3 fluoropyrimidines used in chemotherapy?
5-FU
Capecitabine
TAS-102
Of the antimetabolites, what are the 2 deoxycytidine analogs used in chemotherapy?
Cytarabine
Gemcitabine
Of the antimetabolites, what are the 4 purine antagonists used in chemotherapy?
6-thiopurines:
6-mercaptopurine (6-MP)
6-thioguanine (6-TG)
Other:
Fludarabine
Cladribine
Categories of chemotherapy drugs considered natural products
Vinca alkaloids
Taxanes and other anti-microtubule drugs
Epipodophyllotoxins
Camptothecins
Of the natural products used in chemotherapy, name the 3 vinca alkaloids
Vinblastine
Vincristine
Vinorelbine
Of the natural products used in chemotherapy, name the 5 taxanes and other antimicrotubule drugs
Paclitaxel Docetaxel Cabazitaxel Ixabepilone Eribulin
Of the natural products used in chemotherapy, name the epipodophyllotoxin
Etoposide
Of the natural products used in chemotherapy, name the camptothecins
Topotecan
Irinotecan
Name the anti-tumor antibiotics
Anthracyclines: doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone, derazoxane
Mitomycin (myotmycin C)
Bleomycin
5 tyrosine kinase inhibitors used in chemotherapy
Imatinib Dasatinib Nilotinib Bosutinib Ponatinib
Growth factor receptor inhibitors used in chemotherapy
Cetuximab Panitumumab Necitumumab Erlotinib Afatinib Osimertinib Bevacizumab Ziv-aflibercept Ramucirumab Sorafenib Sunitinib Pazopanib
Most widely used alkylating agent with high oral bioavailability, administered by IV or orally, and activated to the 4-hydroxy intermediate
Cyclophosphagmide
Cyclophosphamide is activated to become 4-hydroxycyclophosphamide, which travels alongside aldophosphamide in circulation. What is the fate of these molecules in liver and tumor tissue?
4-hydroxycyclophosphamide is inactivated in liver or tumor tissue (inactive metabolites include 4-ketocyclophosphamide and carboxyphosphamide)
Aldophosphamide cleaves spontaneously in tumor tissue generating the toxic metabolites (toxic metabolites include phosphoramide mustard and acrolein)
AEs of cyclophosphamide
Phosphoramide mustard responsible for antitumor effects
Acrolein causes hemorrhagic cystitis
Patients should receive vigorous IV hydration during high-dose treatment
Cyclophosphamide has broad clinical applications. What are some of them?
Essential component of many effective drug combinations for: NHL, other lymphoid malignancies, breast and ovarian cancers, solid tumors in children
Burkitt lymphoma — complete remissions and presumed cures when given as a single agent
Used in combo with doxorubicin an da taxane as adjuvant therapy after surgery for breast cancer
First clinically used nitrogen mustard
Most reactive of drugs in its class
Clinical application include topical use for tx of cutaneous T cell lymphoma (CTCL)
Largely replaced by more stable chemotherapeutics
Mechlorethamine
Melphalan is not a vesicant and has inconsistent absorption orally so it is given by IV. What are adverse effects of melphalan?
Toxicity is mostly hematologic
NOTE: N/V and alopecia are less frequent vs. other chemotherapeutics
Clinical application of melphalan
Primarily used to treat multiple myeloma with dexamethasone
Oral chemotherapeutic that is administered orally, considered to have adequate and reliable absorption
It is usually well tolerated in small daily doses, although N/V can occur in a single daily dose >20mg
Clinically used to tx chronic lymphoblastic leukemia (CLL)
Chlorambucil
Describe nitrosureas as a class in terms of cross resistance with other alkylating agents, lipid solubility and related clinical implications, and chemical moieties generated
Not cross resistant with other alkylating agents
Lipid soluble — can cross the blood brain barrier making them effective at treating brain tumors
Generate both alkylating and carbamylating moieties
Major action and lipid solubility of carmustine
Major action is its alkylation of DNA — this can be repaired by MGMT
Highly lipophilic — crosses BBB
AEs of carmustine
Profound and delayed myelosuppression — recovery 4-6 weeks after a single dose
In high doses with bone marrow rescue, carmustine produces hepatic VOD, pulmonary fibrosis, renal failure, and secondary leukemia
Clinical applications of carmustine
Malignant gliomas (implantable carmustine wafer); [Methylation of the MGMT promoter inhibits its expression of 30% of primary gliomas]
Associated with sensitivity to carmustine and other nitrosoureas
Chemotherapeutic with high affinity for cells of islets of Langerhans, causing diabetes in experimental animals
Used clinically to tx human pancreatic islet cell carcinoma and carcinoid tumors
Streptozocin
AEs of streptozocin
Frequent nausea
Mild reversible renal or hepatic toxicity occurring in approx 2/3 of cases (10% will have cumulative dose renal toxicity that can lead to renal failure)
Aziridine chemotherapeutic that is rapidly converted by hepatic CYPs to its desulfurated primary metabolite; used for high-dose chemotherapy regimens in transplants for hematological malignancies
Thiotepa (primary metabolite = TEPA)
[both thiotepa and TEPA from DNA cross links]
AEs of thiotepa
Little toxicity other than myelosuppression
AEs at high doses include mucosal and CNS toxicity, coma and seizures
Orally administered alkylsulfonate chemotherapeutic used to treat chronic myeloid leukemia
Busulfan
AEs of busulfan
At the standard dose — causes myelosuppression
At high doses — causes pulmonary fibrosis, GI mucosal damage, and hepatic VOD (veno-occlusive disease)
When a pt is receiving chemotherapy with busulfan, what drugs are given concomitantly and why?
Anti-convulsants — to protect against acute CNS toxicities
Phenytoin — increases GSTs that metabolize busulfan; reduces AUC by 20%
Non-enzyme inducing benzodiazepines recommended (lorazepam and clonazepam)
Non-classic alkylating agent with incompletely understood MOA; converted by CYP mediated oxidative metabolism to highly reactive alkylating species that methylate DNA; can produce chromosomal damage including chromatid breaks and translocations consistent with its mutagenic and carcinogenic actions, inhibits DNA, RNA, and protein biosynthesis, prolongs interphase (cell cycle), produces chromosome breaks
Procarbazine
Resistance to procarbazine develops rapidly when its used as a single agent (i.e., increased expression of MGMT). What are other AEs of procarbazine?
Carcinogenic potential higher than that of other alkylating agents
Increased risk of secondary cancers — acute leukemia
Augments sedative effects — concomitant CNS suppressants should be avoided
Disulfuram-like actions — avoid alcohol
Clinical applications of procarbazine
Used in the MOPP regimen for Hodgin disease
Also used in treating gliomas as a part of the PVC regimen (procarbazine + vincristine + lomustine [CCNU])
The prodrug of ______ functions as a methylating agent after being converted to monomethyl triazeno metabolite MTIC
Resistance develops due to __________
It is administered parenterally
Dacarbazine
Removal of methyl groups by MGMT
AEs of dacarbazine
Myelosuppression
N/V (90% of pts) — vomiting develops 1-3 hours after treatment and may last up to 12 hours; can be severe
Flu-like syndrome may occur
Clinical application of dacarbazine
Primary indication = Hodgkin disease
Modestly effective against malignant melanoma and adult sarcomas
MOA of bendamustine
Forms cross-links with DNA resulting in single and double stranded breaks —> inhibition of DNA synthesis and function
Inhibits mitotic check points and induces mitotic catastrophe —> cell death
Bendamustine’s cross resistance with other alkylating agents is only partial. What are adverse effects of Bendamustine?
Myelosuppression (rapidly reversible)
Mucositis (rapidly reversible)
Mild nausea and vomiting
Clinical applications of bendamustine
Approved for tx of CLL (chronic lymphoblastic leukemia) and non-Hodgkin lymphoma
MOA of the alkylating agents that are platinum analogs
[precise MOA unknown]
Kills tumor cells in all stages of the cell cycle
Binds DNA through formation of intra- and inter-strand cross links
Inhibits DNA synthesis and function
Platinum analog alkylating agents exhibit synergism with other alkylating agents, ______, and ______
Fluoropyrimidines; taxanes
Platinum analog only given by IV, requiring preceding tx with chloride diuresis via 1-2L NS to prevent renal toxicity, as well as vigorous IV hydration
Cisplatin
_____ inactivates cisplatin, thus the drug should not come into contact with needles or other infusion equiment containing it
Aluminum
T/F: cisplatin has abundant CNS penetration
False — it is found in highest concentrations in kidney, liver, intestine, and testes
It has poor CNS penetration
AEs of cisplatin
Nephrotoxicity [diminished by pretreatment with hydration and chloride diuresis]
Ototoxicity — manifests as tinnitus and leads to high frequency hearing loss
N/V occur in almost all pts
High doses/multiple tx may lead to progressive peripheral motor and sensory neuropathy (may worsen after discontinuation)
Mild to moderate disturbances in electrolytes — tubular damage may lead to renal electrolyte wasting and may produce tetany if untreated
Anaphylactic rxns may occur w/i minutes after administration (facial edema, bronchoconstriction, tachycardia, hypotension)
Treatment with cisplatin can lead to the development of what hematologic malignancy, usually 4+ years after treatment?
AML
How is the common adverse effect of N/V managed during cisplatin tx, as well as tx with other chemotherapy drugs?
5-HT3 receptor antagonists
NK1 receptor antagonists
High dose corticosteroids
Clinical applications for cisplatin therapy
Cisplatin in combo with bleomycin or etoposide (and with added vinblastine) cures 90% of pts with testicular cancer
Cisplatin used with paclitaxel induces complete response in majority of pts with ovarian carcinoma
Other cancers that respond to cisplatin: bladder, head and neck, cervix, endometrium, lung, rectal, anal, childhood neoplasms
______ has a similar MOA, resistance, and spectrum of activity as cisplatin but is a very different chemically, pharmacokinetically, and in terms of toxic properties. It is given IV and does NOT require vigorous IV hydration like cisplatin does
Carboplatin
AEs of carboplatin
Well tolerated clinically with less nausea, neurotoxicity, ototoxicity and nephrotoxicity than cisplatin
Dose limiting toxicity is myelosuppression —> thrombocytopenia
Hypersensitivity reaction — managed by administering graded doses of the drug and more prolonged infusions which lead to desensitization
Clinical applications of carboplatin
Carboplatin and cisplatin are equally effective in the tx of debulked ovarian cancer, non-small cell lung cancer, extensive-stage small cell lung cancer
Used with paclitaxel to induce complete response in majority of ovarian carcinoma
In terms of germ cell, head and neck, and esophageal cancers — which is more effective: carboplatin or cisplatin?
Cisplatin
Carboplatin can be an effective alternative to cisplatin in pts with what conditions?
Impaired renal function
Refractory nausea
Significant hearing impairment
Neuropathy
Oxaliplatin has the same mechanism as the other platinum analogs. What are some adverse effects of oxaliplatin?
Peripheral sensory neuropathy (acute form vs. cumulative dose)
Nausea is well controlled with 5-HT3 receptor antagonists
May cause leukemia and pulmonary fibrosis months to years after administration
May elicit an allergic response — urticaria, hypotension, and bronchoconstriction
Describe acute vs. cumulative dose forms of peripheral sensory neuropathy caused by oxaliplatin
Acute form: often triggered by exposure to cold liquids; paresthesias or dysesthesias in the upper and lower extremities, mouth, and throat
Cumulative dose: similar to cisplatin neuropathy; progressive sensory neurotoxicity — dysesthesias, ataxia, numbness of extremities
Clinical applications of oxaliplatin
Colorectal and gastric cancer
Oxaliplatin suppresses expression of _____ _____, which may be the rationale for the synergy with 5-FU. Oxaliplatin is approved in combination with 5-FU for _________ cancer
Thymidylate synthase (TS); colorectal
MOA of methotrexate
Folic acid analog that binds to the active site of dihydrofolate reductase
Inhibits synthesis of tetrahydrofolate (THF) [the one-carbon carrier for de novo synthesis of thymidylate, purine nucleotides, and amino acids serine and methionine]
Interference in formation of DNA, RNA, and key cell proteins
[Folyl polyglutamate synthase (FPGS) catalyzes formation of intracellular polyglutamate metabolites which are selectively retained in cancer cells]
4 Resistance mechanisms to methotrexate
Decreased drug transport via reduced folate carrier or folate receptor protein
Decreased formation of cytotoxic methotrexate polyglutamates
Increased levels of target enzyme DHFR through gene amplification and other genetic mechanisms
Altered DHFR protein with reduced affinity for methotrexate
Methotrexate may be administered IV, intrathecal, or orally. What 4 drugs inhibit the renal excretion of methotrexate, thus leading to increased risk of methotrexate toxicity?
Aspirin
NSAIDs
Penicillin
Cephalosporins
Methotrexate action can be reversed by administration of reduced folate ________, a drug sometimes used in conjunction with high dose methotrexate therapy to rescue normal cells from undue toxicity
Leucovorin
Clinical applications of methotrexate
Breast cancer
Head and neck cancer
Osteogenic sarcoma
Primary CNS lymphoma
Non-Hodgkins lymphoma
Bladder cancer
Choriocarcinoma
Antimetabolite chemotherapeutic active in the S-phase and transported into the cell via reduced folate carrier and requires activation by FPGS to yield higher polyglutamate forms (like methotrexate)
Pemetrexed
MOA of pemetrexed
Inhibition of thymidylate synthase (TS)
Targets and inhibits DHFR and enzymes involved in de novo purine nucleotide biosynthesis
Adverse effects of pemetrexed
Myelosuppression, skin rash, mucositis, diarrhea, fatigue, and hand-foot syndrome (painful erythema and swelling — tx with dexamethasone)
Vitamin supplement with _____ and _____ significantly reduces toxicities associated with pemetrexed and pralatrexate
Folic acid and vitamin B12
Clinical applications of pemetrexed
Mesothelioma
Approved for use in combo with cisplatin for the first-line tx of NSCLC and as maintenance therapy in pts with NSCLC whose disease has not progressed after 4 cycles of platinum-based chemotherapy
Antimetabolite similar to methotrexate in that it is transported into the cell via reduced folate carrier (RFC) and requires activation by FPGS to yield higher polyglutamate forms, but designed to be more potent substrate for the RFC and FPGS
Pralatrexate
MOA of pralatrexate
Inhibits DHFR
Inhibits enzymes involved in de novo purine nucleotide biosynthesis
Inhibits thymidylate synthase
AEs of pralatrexate
Myelosuppression, skin rash, mucositis, diarrhea, fatigue
Clinical application for pralatrexate
Approved for tx of relapsed or refractory peripheral T-cell lymphoma
Active metabolites of 5-FU and their MOA
FdUMP — binds and forms a ternary complex with TS and reduced 5,10-methylenetetrahydrofolate; inhibition of DNA synthesis through “thymineless death”
FUTP — incorporated into RNA where it interferes with RNA processing and mRNA translation
FdUTP — incorporated into DNA resulting in inhibition of DNA synthesis and function
5-FU is administered IV and has an extremely _____ half life; it is catabolized by the enzyme ___________
Short (10-15 mins)
Dihydropyrimidine dehydrogenase (DPD)
[AR syndrome associated with partial or complete deficiency of the DPD gene seen in 5% of pts — leads to toxicities of myelosuppresion, GI toxicity with diarrhea/mucositis, and neurotoxicity]
AEs of 5-FU
Myelosuppression
GI toxicity (diarrhea/mucositis)
Skin toxicity (hand-foot syndrome)
Neurotoxicity
Clinical applications of 5-FU
Activity against a wide range of solid tumors — breast, stomach, pancreas, esophagus, liver (hepatocellular), head and neck, and anus
Most widely used drug in the tx of colorectal cancer (both as an adjuvant and for advanced disease)
5-FU
Prodrug metabolized to 5-FU in the cancer cell by thymidine phosphorylase, at which time MOA is the same as 5-FU
Capecitabine
The expression of thymidine phosphorylase is higher in what type of tumors (as opposed to normal tissue)?
Solid tumors (e.g., breast, colorectal cancer)
AEs of capecitabine
Main AEs = diarrhea, hand-foot syndrome
Others that occur but less frequently than with 5-FU: myelosuppression, N/V, mucositis, and alopecia
Clinical applications of capecitabine
Metastatic breast cancer as single agent, or combined with others (docetaxel, paclitaxel, lapatinib, ixabepilone, and trastuzumab)
Approved for use in adjuvant therapy of stage III and high risk stage II colon cancer
Metastatic colorectal cancer in combo with irinotecan and oxaliplatin
The XELOX regimen is considered first line tx for metastatic colorectal cancer. What is included in this regimen?
Capecitabine + oxaliplatin
[also used in adjuvant setting for stage III and high-risk stage II colon cancer]
TAS-102 is a prodrug that is inactive in its parent form; an antimetabolite approved in 2015. What are its components?
Trifluridine/tipiracil (1:0.5 ratio)
Trifluridine is a fluorinated pyrimidine nucleoside analog that is metabolized to the monophosphate form — inhibits thymidylate synthase (TS) although much weaker than FdUMP; when metabolized into the triphosphate form, it is directly incorporated into DNA and inhibits its synthesis and function
Tipiracil is a thymidine phosphorylase (TP) inhibitor [key enzyme in degrading trifluridine to inactive forms] which leads to higher levels of trifluridine
Clinical applications for TAS-102
Approved for use in progressive, refractory colorectal cancer
[retains clinical activity in the setting of wild-type and mutant RAS colorectal cancer]
Dose-limiting toxicity and other adverse effects of TAS-102
Myelosuppression (neutropenia more commonly observed than anemia and thrombocytopenia)
Other AEs: GI toxicity with diarrhea and N/V, fatigue, anorexia
S-phase specific antimetabolite converted to the 5’-mononucleotide (ara-CMP) by deoxycytidine kinase which is further metabolized to diphosphate and triphosphate metabolites
Cytarabine
[the triphosphate metabolite (ara-CTP) is thought to be main cytotoxic metabolite]
MOA of cytarabine
Ara-CTP competitively inhibits DNA polymerase-alpha (blockade of DNA synthesis) and DNA polymerase-beta (blockade of DNA repair)
Ara-CTP also incorporated into DNA —> interference with chain elongation; defective ligation of fragments of newly synthesized DNA
Ara-CTP also incorporated into RNA
An important consideration regarding cytarabine is that it is rapidly degraded, but cellular retention of ara-CTP correlates with its lethality to malignant cells — so it is often given by continuous infusion. What are some adverse effects of cytarabine therapy?
Myelosuppression
Mucositis
N/V
Neurotoxicity (high dose)
Clinical applications of cytarabine
Activity is limited to hematologic malignancies, including AML and NHL
[No activity against solid tumors!]
Fluorine-substituted deoxycytidine analog that is phosphorylated by deoxycytidine kinase to the monophosphate form, or by other nucleoside kinases to diphosphate and triphosphate nucleotide forms
Gemcitabine
MOA of gemcitabine diphosphate and triphosphate metabolites
Gemcitabine diphosphate — inhibition of ribonucleotide reductase (reduces level of deoxyribonucleoside triphosphates needed for DNA synthesis)
Gemcitabine triphosphate — inhibits DNA polymerase-alpha (blockade of DNA synthesis) and DNA polymerase-beta (blockade of DNA repair); incorporates into DNA leading to inhibition of DNA synthesis and function
Gemcitabine has dose-limiting toxicity of myelosuppression in the form of neutropenia. It also has AEs of N/V (70% of pts) and a flu-like syndrome. What are some clinical applications of gemcitabine?
Broad spectrum activity against both solid tumors and hematologic malignancies
Initially approved for use in advanced pancreatic cancer
Widely used to treat many different cancers — NSCLC, bladder cancer, ovarian cancer, soft tissue sarcoma, NHL
6-thiopurines are metabolized by the enzyme _____ ______, thus loss of this enzyme alters the metabolism of thiopurines and can result in increased toxic effects including myelosuppression and GI toxicity with mucositis and diarrhea
Thiopurine methyltransferase (TPMT)
6-mercaptopurine (6-MP) is a purine antagonist inactive in its parent form, metabolized hy hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to form monophosphate nucleotide 6-thioinosinic acid. What is the MOA of the active metabolites?
Monophosphate nucleotide 6-thioinosinic acid inhibits several enzymes of de novo purine nucleotide synthesis
Triphosphate form incorporated into both DNA and RNA
6-MP is converted to its inactive metabolite (6-thiouric acid) by an oxidation reaction catalyzed by _____ _____.
Thus, the purine analog _______, a potent inhibitor of the above enzyme, is frequently used as a supportive care measure in the tx of acute leukemias to prevent the development of hyperuricemia that often occurs after tumor cell lysis
Xanthine oxidase
Allopurinol
[note that simultaneous therapy with allopurinol and 6-MP would result in increased levels of 6-MP and excessive toxicity]
Single clinical application of 6-MP
Childhood acute leukemia
MOA of 6-thioguanine (6-TG)
Inhibits several enzymes in the de novo purine nucleotide biosynthetic pathway
Inhibition of purine nucleotide interconversion
Decrease in intracellular levels of guanine nucleotides —> inhibition of glycoprotein synthesis
Interference with the formation of DNA and RNA
Incorporation of thiopurine nucleotides into both DNA and RNA
6-TG synergizes with ______ in the treatment of adult acute leukemia. It is converted to an inactive metabolite by the process of _______
Cytatabine; deamination
Fludarabine is a purine antagonist that is phosphorylated intracellularly by deoxycytidine kinase to the monophosphate and eventually converted to the triphosphate form. What is the MOA of these metabolites?
Fludarabine triphosphate — interferes with process of DNA synthesis and DNA repair through inhibition of DNA polymerase-alpha and beta. Directly incorporated into DNA, resulting in inhibition of DNA synthesis and function
Fludarabine diphosphate — inhibits ribonucleotide reductase leading to an inhibition of the production of essential deoxyribonucleotide triphosphates
Induces apoptosis in susceptible cells through a yet to be determined mechanism of action
Dose limiting toxicity and other AEs of fludarabine
Dose limiting = myelosuppression
AEs:
Potent immunosuppressant —> increased risk for opportunistic infections; pneumocystis jiroveci pneumonia (PCP)
[PCP prophylaxis with TMP/SMX at least 3x/week; prophylaxis should continue up to 1 week after stopping fludarabine tx]
Clinical applications of fludarabine
Low-grade NHL
Chronic lymphocytic leukemia
Purine nucleoside analog with high specificity for lymphoid cells; inactive in its parent form — initially phosphorylated by deoxycytidine kinase to the monophosphate form and eventually metabolized to the triphosphate form
Cladribine
MOA of cladribine triphosphate metabolite
Directly incorporated into DNA, resulting in inhibtion of DNA synthesis and function; interferes with the process of DNA synthesis and repair through inhibition of DNA polymerase alpha and beta
The main toxicity of cladribine is _______.
Cladribine is administered as a continuous 7-day infusion, and there is very manageable side effect profile under these conditions
However, a decrease in ____ and _____ cells can last over 1 year
Myelosuppression
CD4; CD8
Clinical applications for cladribine
Hairy cell leukemia
Other low-grade lymphoid malignancies — CLL and NHL
MOA of vinca alkaloids class of chemotherapeutics
Inhibit tubulin polymerization, disrupting assembly of microtubules (especially those involved in mitotic spindle, leading to mitotic arrest in metaphase, leading to cell death)
M-phase specific!
Microtubules also have important roles in maintaining cell shape and protein transport, so disruptions in these processes can lead to cell death as well
Vinca alkaloid derived from periwinkle plant Vinca rosea, used in Hodgkins and non-hodgkins lymphomas, breast cancer, and germ cell cancers
Vinblastine
AEs of vinblastine
N/V
Bone marrow suppression
Alopecia
Potent vesicant (blistering)
Vinca alkaloid derived from the periwinkle plant Vinca rosa. Clinical uses include pediatric acute lymphoblastic leukemia (in combo with prednisone), Hodgkins and non-hodgkins lymphoma, multiple myeloma, and pediatric tumors including rhabdomyosarcoma, neuroblastoma, Ewing’s sarcoma, and Wilm’s tumor
Vincristine
[Vincristine is closely related structurally to vinblastine with similar MOA, mech of resistance, and clinical pharmacology, but different in terms of clinical activity and safety profile]
Vincristine has a higher affinity for _____ microtubules
Axonal
Dose limiting toxicity of vincristine
Neurotoxicity (usually peripheral sensory neuropathy)
— can be ANS dysfunction with orthostatic hypotension, urinary retention, paralytic ileus or constipation, cranial nerve palsies, ataxia, seizures, coma
Aside from its dose-limiting toxicity of neurotoxicity, what are some other AEs of vincristine?
Myelosuppression (although milder and less significant that vinblastine)
SIADH
Semisynthetic derivative of vinblastine with same MOA as vinblastine and vincristine; used in NSCLC, breast cancer, and ovarian cancer
Vinorelbine
Dose limiting toxicity and AEs associated with vinorelbine
Dose limiting: Myelosuppression with neutropenia
AEs: N/V, transient elevations in LFTs, neurotoxicity, and SIADH
Natural products like the taxanes and other anti-microbial drugs work in the ____ phase of the cell cycle
M phase
Alkaloid ester derived from the Pacific yew (Taxus brevifolia) and the European yew (Taxus baccata) that acts as a mitotic spindle poison, binding with high affinity to microtubules with enhancement of tubulin polymerization, leading to inhibition of mitosis and cell division
Paclitaxel
Acute and delayed dose-limiting toxicities associated with paclitaxel
Acute — N/V, hypotension, arrhythmias, hypersensitivity
Delayed — myelosuppression, peripheral sensory neuropathy
Hypersensitivity reactions to paclitaxel are observed in 5% of pts. The incidence of these are significantly reduced by premedication with _____, _____, AND _______
Dexamethasone, diphenhydramine, H2 blocker
What are the benefits of the albumin-bound paclitaxel nanoparticle formulation?
Not associated with hypersensitivity reactions
Reduced myelosuppressive effects compared with paclitaxel
Neurotoxicity is more readily reversed when compared with paclitaxel
Clinical applications of paclitaxel
Broad range of solid tumors:
Ovarian, advanced breast, NSCLS and small cell lung cancer
Head and neck, esophageal, prostate, and bladder
AIDS-related Kaposi’s sarcoma
Semisynthetic taxane derived from the European yew tree with identical MOA, metabolism, and elimination to paclitaxel; approved as second line therapy in advanced breast cancer and NSCLC, with major activity in head and neck cancer, small cell lung cancer, gastric cancer, advanced platinum-refractory ovarian cancer, and bladder cancer
Docetaxel
Acute vs. delayed toxicities of docetaxel
Acute: hypersensitivity
Delayed: neurotoxicity, fluid retention, myelosuppression with neutropenia
Semisynthetic taxane with identical MOA, metabolism, and elimination to other taxanes, but a unique characteristic is that it is a poor substrate for P-glycoprotein, making it useful for treating multi-drug resistant tumors
Cabazitaxel
Major toxicities of cabazitaxel
Myelosuppression
Neurotoxicity
Allergic reactions
Semisynthetic epothilone B analog (NOT a taxane) that acts as a microtubule inhibitor, binding directly to beta-tubulin subunits leading to dynamic inhibition of normal microtubule function
Ixabepilone
Ixabepilone is active in the M phase of the cell cycle and has activity in resistant tumors with _____ mutations and overexpression of __________
Tubulin; P-glycoproteins
AEs of ixabepalone
Myelosuppression
Hypersensitivity
Neurotoxicity (peripheral sensory neuropathy)
Clinical applications of ixabepilone
Approved for metastatic breast cancer (as a monotherapy or in combo with capecitabine)
Synthetic analog of halichondrin B, works to inhibit microtubule function leading to block in the G2-M phase of the cell cycle
Eribulin
Eribulin is less sensitive to P-glycoprotein, so it has activity in tumors overexpressing P-glycoprotein. It is approved for what type of cancer?
Metastatic breast cancer
Semisynthetic derivative of podophyllotoxin, extracted from mayapple root (Podophyllum peltatum); available in IV and oral formulations for the tx of germ cell cancer, small cell and NSCLC, Hodgkins and nonhodgkins lymphoma, and gastric cancer
Etoposide
MOA of etoposide
Forms a complex with topoisomerase II and DNA, leading to inhibition of the activity of topoisomerase II and subsequent inactivation of DNA synthesis and function
Major acute vs. delayed toxicities of etoposide
Acute: N/V, hypotension
Delayed: alopecia, myelosuppression
Natural Chinese tree-derived class of chemotherapeutics that work by inhibiting the activity of topoisomerase I, resulting in DNA damage
Camptothecins (topotecan and irinotecan)
AEs of camptothecans (topotecan and irinotecan)
Myelosuppression and diarrhea
[early form of diarrhea occur within 24 hrs of administration as cholinergic event; may be treated with atropine. Late form of diarrhea occurs 2-10 days later and can be severe — leading to electrolyte imbalances and dehydration]
IV administered camptothecan analog that is indicated for treatment of advanced ovarian cancer as second-line therapy (following initial tx with platinum-based chemotherapy) as well as second-line therapy for small cell lung cancer
Topotecan
Dose limiting toxicity of topotecan
Neutropenia
Irinotecan is a prodrug camptothecan analog, converted by carboxylesterase enzyme to ______ in the ______, a metabolite that is a 1000x more potent topoisomerase I inhibitor vs irinotecan
SN-38; liver
Clinical applications of irinotecan
Approved as first-line therapy when used in combo with 5-FU and leucovorin for metastatic colorectal cancer
[Originally approved as second-line monotherapy for metastatic colorectal cancer]
Little is known about the clinical pharmacology or metabolism of liposomal irinotecan, but it is approved in combination with 5-FU and leucovorin for the treatment of ___________ after disease progression following gemcitabine-based therapy
Adenocarcinoma of the pancreas
[AEs of liposomal irinotecan include myelosuppression and GI toxicity with diarrhea, N/V]
The anthracyclines are anti-tumor antibiotics isolated from Streptomyces peucetius var caesius and are among the most widely used cytotoxic anti-cancer drugs. What is the MOA of anthracyclines?
Inhibition of topoisomerase II
Generation of semiquinone free radicles and oxygen free radicals through iron-dependent, enzyme-mediated reductive process
High affinity binding to DNA through intercalation, with blockade of the synthesis of DNA and RNA, and DNA strand scission
Binding to cell membranes to alter fluidity and ion transport
Part of the MOA of anthracyclines is the generation of semiquinone and oxygen free radicals, this has been well established as the cause of what toxicity associated with this drug class?
Cardiotoxicity
Dose limiting toxicity and other AEs of anthracyclines
Dose-limiting = myelosuppression (neutropenia more common than thrombocytopenia); in some cases dose-limiting factor may be mucositis
Other AEs: cardiotoxicity, radiation recall reaction (erythema and desquamation of the skin observed at sites of prior radiation therapy)
Acute vs. chronic form of cardiotoxicity seen with the anthracyclines
Acute: occurs w/i first 2-3 days. Presents with arrhythmias and conduction abnormalities, other ECG changes, pericarditis, and myocarditis. Transient and often asymptomatic.
Chronic: dose-dependent; dilated cardiomyopathy associated with heart failure, increased production of oxygen free radical production within the myocardium — IMPORTANT: lower the weekly doses or continue infusion to reduce likelihood of this toxicity
_______ is an anthracycline generally combined with cyclophosphamide, cisplatin, and/or 5-FU, as it has greater activity in combination vs. monotherapy
Doxorubicin
Doxorubicin is one of the most important cancer drugs in clinical practice, what are the clinical applications of doxorubicin?
Major clinical activity in cancers of the breast, endometrium, ovary, testicle, thyroid, stomach, bladder, liver, and lung [also soft tissue sarcomas, as well as childhood cancers including neuroblastoma, Ewing’s sarcoma, osteosarcoma, and rhabdomyosarcoma]
Clinical activity in hematologic malignancies: ALL, multiple myeloma, Hodgkins and non-hodgkins lymphomas
______ is the first agent of the anthracycline class to be isolated, and unlike doxorubicin, its efficacy is limited in solid tumors. It is primarily used in tx of AML
Daunorubicin
Semisynthetic antracycline glycoside analog of daunorubicin used in combo with cytarabine for induction therapy of AML
Idarubicin
[when combined with cytarabine, idarubicin is more active than daunorubicin in producing complete remissions and in improving survival in pts with acute myelogenous leukemia]
Anthracycline analog whose mechanism of action and clinical pharm are identical to the others in this class; initially approved for use as a component of adjuvant therapy in early stage, node-positive breast cancer. Also used in tx of metastatic breast cancer and gastroesophageal cancer
Epirubicin
Anthracene compound whose structure resembles the anthracycline ring; works by binding DNA to produce strand breakage and inhibits both DNA and RNA synthesis
Mitoxantrone
Dose limiting and other toxicities associated with mitoxantrone
Dose limiting = myelosuppresion with leukopenia
AEs: mild nausea and vomiting, mucositis, and alopecia
Acute and chronic cardiac toxicity (although less so than docorubicin)
Blue discoloration of the fingernails, sclera, and urine is observed 1-2 days after drug administration
Clinical application of mitoxantrone
Currently used in tx of advanced, hormone-refractory prostate cancer and low-grade-non-Hodgkin’s lymphoma
Indicated in breast cancer and in pediatric and adult acute myeloid leukemias
Iron-chelating agent approved to prevent or reduce anthracycline-induced cardiotoxicity in women with metastatic breast cancer that have received a cumulative dose (>300 mg/m^2) of doxorubicin
Dexrazoxane
Anti-tumor antibiotic isolated from streptomyces caespitosus; metabolically activated via enzyme-mediated reduction, generating an alkylating agent that cross-links DNA (works similar to other alkylating agents)
Mitomycin (mitomycin C)
T/F: Inner solid tumor cells are more sensitive to mitomycin vs. normal cells
True — d/t hypoxic environment conducive to reductive reactions. The reduction of mitomycin to the alkylating agent is more likely to occur within the tumor
Best available drug for use in combination with radiation therapy to attack hypoxic tumor cells
Mitomycin (mitomycin C)
In what phase(s) of the cell cycle is mitomycin active?
All phases
Acute and delayed toxicities associated with mitomycin
Acute: N/V
Delayed: Myelosuppression, mucositis, anorexia and fatigue, hemolytic uremic syndrome
Clinical applications of mitomycin
Squamous cell cancer of the anus in combo with 5-FU and radiation
Intravesical tx of superficial bladder cancer (little systemic absorption of mitomycin when it is used in this way)
Small peptide anti-tumor antibiotic that contains a DNA binding region and an iron-binding domain at opposite ends of the molecule; clinically indicated for Hodgkin’s and non-hodgkins lymphomas, germ cell tumors, head and neck cancer, squamous cell cancer of the skin, cervix, and vulva
Bleomycin
MOA of bleomycin
Binds to DNA resulting in single and double strand breaks following free radical formation
Binds to DNA and inhibits DNA biosynthesis
DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex —> chromosomal aberrations
The MOA of bleomycin causes accumulation of cells in the ____ phase of the cycle
G2
Dose-limiting toxicity and other AEs associated with bleomycin
Dose-limiting: pulmonary toxicity (pneumonitis w/ cough, dyspnea, dry inspiratory crackles, infiltrates on CXR)
AEs: acute include allergic reactions and hypotension; delayed include skin toxicity, pulmonary fibrosis, mucositis, and alopecia
In rare cases, the pulmonary toxicity that occurs with bleomycin therapy may be fatal. What factors increase the risk of experiencing pulmonary toxicity on bleomycin therapy?
Age >70
Cumulative dose >400 units
Underlying pulmonary disease
Prior mediastinal or chest irradiation
Describe metabolism of the tyrosine kinase inhibitors and the drug and dietary implications of this
TK inhibitors are metabolized by CYP3A4 in the liver
Drug-drug interactions occur with medications that are also elminated by this route
Pts on these drugs should avoid grapfruit products, starfruit, and pomelos (which may inhibit metabolism of the TK inhibitors)
TK inhibitor that works as inhibitor of Bcr-Abl oncoprotein, preventing phosphorylation of the kinase substrate by ATP; also inhibits other RTKs for platelet-derived growth factor receptor (PDGFR) and c-kit
Imatinib
Acute and delayed toxicities associated with imatinib
Acute: N/V
Delayed: fluid retention with ankle and periorbital edema, diarrhea, myalgias, CHF
Clinical applications for imatinib
CML (philadelphia chromosomal translocation t9:22)
GI stromal tumors expressing the c-kit tyrosine kinase
First line therapy in chronic phase CML, in blast crisis, and as second-line therapy for chronic phase CML that has progressed on prior IFN-alpha therapy
Imatinib
Inhibitor of several tyrosine kinases including Bcr-Abl, c-kit, and PDGFR-beta; differs from imatinib in that it binds to the active and inactive conformations of the Abl kinase domain (thus it can overcome imatinib resistance resulting from mutations in Bcr-Abl)
Dasatinib
[thus clinical applications of dasatinib are CML and philadelphia chromosome positive ALL with resistance or intolerance to imatinib therapy]
Second generation phenylamino-pyrimidine molecule that inhibits Bcr-Abl, c-kit, and PDGFR-beta tyrosine kinases; differs from imatinib with higher affinity for the Abl kinase (thus overcoming imatinib resistance resulting from Bcr-Abl mutations)
Nilotinib
[thus main clinical use is chronic phase and accelerated phase CML with resistance or intolerance to prior therapy including imantinib; Also recently approved as first-line therapy in chronic phase CML]
Inhibitor of Bcr-Abl tyrosine kinase that retains activity in 16 of the 18 imatinib-resistant Bcr-Abl mutations, but is not effective against T315I and V299L mutations which reside in the ATP-binding domain of the Abl tyrosine kinase
Bosutinib
AEs of bosutinib
Acute: N/V
Delayed: diarrhea, fluid retention, myelosuppression, skin rash, hepatotoxicity
Clinical applications of bosutinib
Adult pts with chronic, accelerated, or blast phase Ph chromosome-positive CML with resistance or intolerance to prior therapy
Inhibitor of all known mutant forms of Bcr-Abl (including gate keeper mutation T315l) tyrosine kinase as well as other kinases including VEGF-R, PDGF, FGF, Flt3, TIE-2, Src family kinases, Kit, TET, and EPH
Ponatinib
FDA approved clinical application of Ponatinib
Adult pts with chronic, accelerated, or blast phase CML that is resistant or intolerant to prior TKI therapy and also approved for Ph+ ALL that is resistant or intolerant to prior TKI therapy
_____ is a receptor overexpressed in a number of solid tumors. Its activation and downstream signaling lead to cell growth and proliferation, invasion and metastasis, and angiogenesis. Signaling at this receptor inhibits the cytotoxic activity of various anti-cancer agents and radiation therapy leading to suppression of key apoptotic mechanisms and the development of cellular drug resistance.
Epidermal growth factor receptor (EGFR)
VEGF is an angiogenic growth factor whose signaling pathway is an attractive target for chemotherapy. What are some general methods to inhibit VEGF signaling?
Inhibition of interaction of VEGF with its receptor — target VEGF ligand w/ Abs, compete with VEGF receptors for VEGF w/soluble chimeric decoy receptors
Direct inhibition of VEGF receptor-associated tyrosine kinase activity by small molecule inhibitors
Chimeric monoclonal Ab directed against the extracellular domain of EGFR; used in combination with irinotecan and G1 isotype has antitumor activity mediated in part by immunologic-mediated mechanisms
Cetuximab
The efficacy of cetuximab is restricted to those pts whose tumors express the wild-type _____ gene
RAS (includes both KRAS and NRAS)
Adverse effects of cetuximab
Generally well tolerated
Acneiform skin rash
Hypersensitivity infusion reaction
Hypomagnesemia
Clinical applications of cetuximab
Combined with irinotecan for metastatic colon cancer in the refractory setting or as monotherapy in pts who are deemed to be irinotecan-refractory
Combined with irinotecan+oxaliplatin in first line tx of metastatic colorectal cancer
Approved for use in combo with radiation therapy in pts with locally advanced head and neck cancer (BLACK BOX WARNING of increased risk of sudden death when combined with radiation for head/neck cancer)
Fully human monoclonal antibody directed against EGFR, MOA is inhibition of EGFR signaling pathway but the G2 isotype of this drug is not expected to exert any immunologic-mediated effects
Panitumumab
The efficacy of panitumumab is restricted to those patients whose tumors express the wild-type ___ gene. Panitumumab can be combined with _____
RAS; irinotecan
Adverse effects of panitumumab
Acneiform skin rash and hypomagnesemia
Infusion related reactions can occur but are less common than cetuximab bc panitumumab is fully human antibody
Clinical applications for panitumumab
Originally approved for pts with refractory metastatic CRC who have been tx with all other active agents
Approved for use with the FOLFOX chemotherapy regimen in the front-line treatment of metastatic CRC [FOLFOX = oxaliplatin + 5-FU + folinic acid (leucovorin)]
Combined with irinotecan-based therapy in second-line tx of metastatic CRC
Fully human IgG1 monoclonal Ab directed against EGFR; the G1 isotype of this drug has antitumor activity mediated in part by immunologic-mediated mechanisms
Necitumumab
Necitumumab has the same adverse effects as cetuximab and panitumab with the addition of increased risk of _____ and _____ events
Venothrombolic; arterioembolic
Clinical application for necitumumab
Approved for use in combo with gemcitabine and cisplatin chemotherapy for the tx of squamous NSCLC
Small molecule inhibitor of the tyrosine kinase domain associated with EGFR, metabolized by CYP3A4 (potential for drug interactions with things like phenytoin and warfarin; grapefruit products)
Erlotinib
Erlotinib is often combined with _______
Patients who are ______ are more responsive to erlotinib
Gemcitabine
Nonsmokers
AEs of erlotinib include acneiform rash, diarrhea, anorexia, and fatigue. What are its clinical applications?
First-line tx of metastatic NSCLC in pts with EGFR mutations and in pts that are refractory to at least one prior chemotherapy regimen
Maintenance therapy of pts with metastatic NSCLC whose disease has not progressed after 4 cycles of platinum-based chemotherapy
Approved for use in combo with gemcitabine for the treatment of advanced pancreatic cancer
Small molecule inhibitor of the tyrosine kinase domains associated with EGFR, HER2, and HER4 —> inhibits downstream ErbB signaling
Afatinib
Afatinib has similar toxicities to erlotinib (acneiform rash, diarrhea, anorexia, fatigue); what is its clinical application?
First-line tx of metastatic NSCLC with EGFR mutations
Small molecule inhibitor that treats metastatic EGFR T790M mutant NSCLC following progression on or after EGFR tyrosine kinase inhibitor therapy; also targets the L858R and exon 19 EGFR mutations
Osimertinib
Osimertinib has similar AEs to erlotinib and afatinib in addition to what unique toxicity?
Cardiotoxicity — QTc prolongation and cardiomyopathy
Recombinant humanized monoclonal antibody that targets all forms of VEGF-A by binding to it and preventing interaction with target receptors
Bevacizumab
Bevacizumab does not exacerbate the toxicities typically observed with cytotoxic chemo; what are th emain concerning AEs with bevacizumab?
HTN
Increased incidence of arterial thromboembolic events (TIA, stroke, angina, MI)
Wound healing complications
GI perforation
Proteinuria
Clinical applications for bevacizumab
Combined with 5-FU and oxaliplatin in tx of metastatic CRC
FDA approved as first-line treatment for metastatic CRC in combo with any IV fluoropyrimidine-containing regimen
Also approved in combo with chemo for metastatic NSCLC and breast cancer
Recombinant fusion protein made up of portions of the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of the human IgG1 molecule (soluble receptor to VEGF-A, VEGF-B, and placental growth factor [PIGF]), binds VEGF-A with significantly higher affinity vs. bevacizumab
Ziv-aflibercept
Ziv-aflibercept has similar adverse effects as bevacizumab. What are its clinical applications?
Used in combo with FOLFIRI regimen for pts with metastatic CRC that has progressed on oxaliplatin-based chemotherapy
IgG1 antibody that targets the VEGF-R2 receptor and inhibits the binding of VEGF-A, VEGF-C, and VEGF-D, thus inhibiting downstream VEGF-R2 signaling
Ramucirumab
Ramucirumab has similar AEs as bevacizumab. What are the clinical applications of ramucirumab?
Advanced gastric or gastroesophageal junction adenocarcinoma, metastatic NSCLC, and metastatic CRC
Small molecule that inhibits multiple RTKs and is metabolized by the CYP3A4 system
Sorafenib
[inhibits VEGF-R2, VEGF-R3, platelet-derived growth factor beta, and raf kinase]
AEs of sorafenib
HTN
Bleeding complications
Fatigue
Skin rash and hand-foot syndrome observed in 30-50%
Clinical applications for sorafenib
Initially approved for renal cell cancer
Also approved for advanced hepatocellular cancer
Similar drug to sorafenib that inhibits multiple RTKs including PDGFR-alpha and beta, VEGF-R1/R2/R3, and c-kit; may be utilized as an alternative to imatinib after tolerance has developed
Sunitinib
Sunitinib is metabolized by CYP3A4 system, so drug interactions must be monitored for. What are the main complications associated with Sunitinib?
HTN
Bleeding complications
Fatigue
Increased risk of cardiac dysfunction — can lead to CHF
Clinical applications for sunitinib
Advanced renal cell cancer
GI stromal tumors after disease progression on or with intolerance to imatinib
Small molecule that inhibits multiple RTKs including VEGF-R2/R3, PDGFR-beta, and raf kinase; metabolized by CYP3A4 system, and is only approved for the tx of advanced renal cell cancer
Pazopanib
[adverse effects include HTN, bleeding complications, and fatigue similar to others in this class]
