Lecture 12: Cancer Pharm Flashcards
What are the phases of the cell cycle and what are happening during each of them?
G0 - resting phase (not actively in the cell cycle)
G1 - synthesis of components for DNA synthesis
S - synthesis of DNA
G2 - synthesis of components needed for mitosis
M -mitosis
Why are the G1 and G2 phases important and what can override each of their arrests?
- G1/G2 phases stop inappropriate cell cycle progression and cause either arrest/entry into G0
oncogene activation overrides G1 arrest
tumor suppressor inactivates overrides G2 arrest
What is Primary Chemotherapy and what are the goals of treatment?
- primary treatment for advanced cancer w/no other alternatives OR advanced metastatic cancer
Goals: relieved symptoms, improve quality of life, prolong time to tumor progression
What cancers are curable via Primary Chemotherapy? (4 for adults and 4 for children)
A: Hodgkin/non-Hodgkin, choriocarcinoma, germ cell tumors, AML
C: Burkitt’s, Wilms’ tumor, embryonal rhabdomyosarcoma, acute lymphoblastic leukemia
What is Neoadjuvent Chemotherapy and what are its goals?
- chemotherapy given before surgery or radiation in order to shrink the size of the primary tumor
- helps spare organs and make resection easier
What is Adjuvent Chemotherapy?
- chemotherapy after local treatments, such as surgery or radiation
- helps prevent local/systemic recurrence and improves overall pt. survival
What are Tissue Growth Fraction/Rate and why are they important to consider when providing chemotherapeutic agents?
Growth Fraction - ratio of proliferating to G0 tumors cells
- antineoplastic agents more effective w/high GF
- growth rate of tumors is rapid at first but decreases over time due to the burden of the tumor (central cells of tumor mass usually in G0 phase)
- by surgically removing or irradiating the tumor, it can be shrunk to inc. its GF, making it MORE susceptible to chemotherapeutic agents
What is the Log Cell Kill Hypothesis? How should therapy be given to prevent excessive damage to patients healthy cells?
- antineoplastic surgery follows 1st order kinetics (give dose destroys a constants FRACTION of cells)
- high-dose intermittent therapy allows normal, healthy tissue to recover while killing the tumor cells
What type of infusion is better suited for cell cycle nonspecific vs cell cycle specific antineoplastics?
Nonspecific –> intermittent high dose therapy
Specific –> continuous infusion (has practical limitations), also drugs with high metabolism or excretion
What are Pharmacological Sanctuaries and how can they be dealt with?
- regions where tumor cells are LESS susceptible to antineoplastic agents (CNS/testes)
- can provide antineoplastics via intracavity/intrathetcal/etc treatment that specifically targets that area or bypasses the normal transport constraints of that location
How many cycles of treatment do most curable tumors require?
6-8 cycles of therapy
Inherent chemotherapeutic resistance vs Acquired chemotherapeutic resistance
ICR: drug resistance in absence of prior exposure
- caused by genomic instability
ACR: in response to exposure to give drug or drug class
- due to genomic change causing amp/supp of gene
Multidrug Resistance and p-Glycoprotein
bonus: what drug can potentially inhibit it?
- MDR1; high baseline expression of PGP correlates with primary/inherent resistance to natural antineoplastic agents
- usually seen in tissues with barrier functions or pharmacological barrier sites (BBB/PBB)
- over-expression leads to acquired drug resistance (Verapamil - Ca channel blocker - may inhibit)
What are 5 common adverse effects that occur with nearly all CLASSIC antineoplastic agents?
nausea, vomiting, fatigue, somatitis (mouth swelling/sores), alopecia (hair loss)
- also see myelosuppression, low sperm counts, depressed development in children
What are 3 things that can help decrease the effects of myelosuppression, nausea/vomiting, and skeletal complications?
Hematopoietic agents - myelosuppression
Serotonin receptor antagonist - nausea/vomiting
Biphosphonates - delay skeletal complications
REST AND RECOVERY
What are 6 common Alkylating agents (CCBPDC) and what is their MOA?
cyclophosphamide, carmustine, busulfan, procarbazine, dacarbazine, cisplatin (has platinum)
**cyclophosphamide is most WIDELY used (most likely to cause vomiting/nausea)
- cell cycle NONSPECIFIC; create Inter- and Intralinkages between AA in DNA (GUANINE) and prevents the unwinding of DNA strands
Activation of cyclophosphamide and potential toxicity
What drug can help prevent toxic effects?
- cyclophosphamide is a prodrug activated by CYP2B
- activated form can be converted to aldophsphamide, which can produce Acrolein (hemorrhagic cystitis)
- MENSA inactivates acrolein and is used for prophylaxis of chemo-induced cystitis
What are pharmacological effects of Alkylating Agent usage and what are specific toxicities caused by cyclophosphamide, cisplatin, and busulfan?
- dose related effects and damage at site of injection (oral preferred)
- most cause nausea/vomiting after 30-60 min, as well as common antineoplastic side effects
Cyclophosphamide - hemorrhagic cystitis
Cisplatin - renal tubular damage/ototoxicity
Busulfan - pulmonary fibrosis
What are common Antimetabolites (MFM) and what is their MOA?
- methotrexate, 5-Fluorouracil, 6-Mercaptopurine
- structural analogs necessary for cell proliferation
- block/subvert pathways involved in cell replication (CELL CYCLE SPECIFIC for S-PHASE)
How does Methotrexate work and why is Leucovorin usually given with it?
- Methotrexate = folic acid analog that blocks Dihydrofolate Reductase (NO DNA synthesis)
- low doses can also be used to treat rheumatoid arthritis and psoriasis
- Leucovorin (reduced folate) is used with HIGH-DOSE methotrexate to rescue normal cells (or accidental overdose)
How does 5-Fluorouracil work? (3 active components)
- prodrug that, once activated, blocks Thymidylate Synthetase (FdUMP) via covalent binding (NO DNA)
- FdTUP/FUTP get incorporated into both DNA and RNA, interfering with synthesis, function, translation, and processing
How does Mercaptopurine (6-MP) work? How does Allopurinol effect it?
- inhibits purine nucleotide synthesis due to triphosphate incorportation (HGRPT = 6-thioinosinic acid)
- first pass effect via xanthine oxidase converts 6-MP to 6-thiouric acid
- simultaneous administration of allopurinol (dec. hyperuricemia) with 6-MP can inhibit xanthine oxidase, causing inc. 6-MP = inc. toxicity (dec. oral 6-MP dose by 50-75%, IV unaffected)
What are pharmacological effects of antimetabolites?
- S-phase specific, but otherwise relative little acute toxicity after initial dose
- common toxicities
What common natural antineoplastic drugs? (VVPEDBL-A)
vinblastine, vincristine, paclitaxel, etoposide, doxorubicin, bleomycin, L-Asparaginase
What is the MOA of Vinca Alkaloids and what are common toxicities of drug use?
- bind to B-tubulin and inhibit microtubule assembly (depolarization); SPECIFIC for M-Phase
Vinblastine - myelosuppression (more so than VinC)
Vincristine - cumulative neurological toxicities (more so than VinB)
- common toxicities: bone marrow depression/alopecia
What is the MOA of Taxanes and what are common toxicities of drug use?
What cancer are they a traditional treatment for?
- bind to B-tubulin and stabilize microtubule formation; SPECIFIC for M-Phase
Paclitaxel - hand/toe hypersensitivity rxns, taste change
Docetaxel - hypersensitivity, neutropenia, hair loss
- greater uptake and retention (less dose/less probs)
Traditional treatment for BREAST CANCER
What drugs are usefully Topoisomerase I and Topoisomerase II inhibitors? What is the cell cycle specificity?
T1: camptothecins (topotecan, irinotecan)
T2: epipodophyllotoxins and anthracycline antibiotics
- etoposide and doxorubicin
S-Phase specific (also G1/G2)
What strain of microbe produces all of the anticancer antibiotics currently in use?
Streptomyces
- most mainly affect DNA
What is the affect of Antracyclines, Bleomycin, and Dacintomycin on tumors?
What are possible side effects of using these drugs?
A: topoisomerase II inhibitor, DNA intercalation
- NONSPECIFIC
- free radicals cause cardiotoxicity (heart failure)
B: single/double stranded breaks; minimal myelosupp.
- significant pulmonary toxicity (PNEUMONITIS)
- G2 specific
D: intercalation of DNA
What is the MOA of L-asparaginase (enzyme), what is it specific for, what are its toxicities, and what cancer is it used to treat?
MOA: hydrolyzes L-asparagine into aspartic acid and ammonia (inhibits protein synthesis)
- G1 phase specific
- causes acute hypersensitivity reactions; inc. clotting/bleeding, pancreatitis in delayed rxns
targeted therapy for ALL (ALL tumor cells lack enzyme asparagine synthetase
Tretinoin and t(15;17)
- t(15;17) creates PML-RARa protein that inhibits granulocytic maturation in APL
- Tretinoin binds to protein and antagonizes the inhibitory effect of in the transcription of target genes, allowing promyelocytes to differentiate into neutrophils and die
- can cause Vitamin A toxicity and retinoic acid syndrome
Imatinib and t(9;22)
- t(9;22) found in 95% of CML pts. (creates BCR-ABL fusion protein –> Tyrosine Kinase ALWAYS ON)
- Imatinib inhibits ABL tyrosine kinase by binding to it, and can ALSO inhibit the RTKs PDGFR and KIT
What are Erlotinib and Geritinib used to treat and how?
- both are Tyrosine Kinase domain inhibitors of the EGFR
- used to treat non-small cell lung cancer and pancreatic cancer
- known to produce dermatologic toxicities
What are the effects of Interferons (Interferon-a2a and a2b) and Interleukin-2 on tumor growth?
- both agents act indirectly and enhance immunologic response to neoplastic cells
Interferons: inhibit cell growth, alter cellular differentiation, inc. macrophage phagocytosis, and augment lymphocyte cytotoxicity
IL-2: inc. cytotoxic killing by T-cells and NK cells
- major toxicity = capillary leak syndrome
Rituximab:
What is its MOA, what is it used to treat, and what are adverse effects of use?
MOA: monoclonal Ab directed against CD20 Ag on normal/malignant B-lymphocytes (complement-mediated lysis –> induction of apoptosis
- treats low-grade or follicular B-cell CD20 NHL
- can cause cytopenia and hypersensitivity rxns
Zif-aflibercept
- recombinant fusion protein made of extracellular domains of human VEGF receptors 1 and 2 bound to IgG1 molecule
- bind VEGF ligands prevents their interactions with receptors leading to inhibition of VEGFR signaling
Malignant Melanoma treatments (5)
Dacarbazine, cisplatin are most active cytotoxic agents (response rate to them is low)
treatment with high dose of IL-2 has lead to cures in a small subset of pts.
Nivolumb and pembrolizumab is approved for unresectable or metastatic melanoma monotherapy
