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SBL (Skin, Blood, Lymph) Exam 1 and 2 > Lecture 12: Cancer Pharm > Flashcards

Lecture 12: Cancer Pharm Flashcards

1
Q

What are the phases of the cell cycle and what are happening during each of them?

A

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

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2
Q

Why are the G1 and G2 phases important and what can override each of their arrests?

A
  • 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

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3
Q

What is Primary Chemotherapy and what are the goals of treatment?

A
  • 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

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4
Q

What cancers are curable via Primary Chemotherapy? (4 for adults and 4 for children)

A

A: Hodgkin/non-Hodgkin, choriocarcinoma, germ cell tumors, AML

C: Burkitt’s, Wilms’ tumor, embryonal rhabdomyosarcoma, acute lymphoblastic leukemia

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5
Q

What is Neoadjuvent Chemotherapy and what are its goals?

A
  • chemotherapy given before surgery or radiation in order to shrink the size of the primary tumor
  • helps spare organs and make resection easier
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6
Q

What is Adjuvent Chemotherapy?

A
  • chemotherapy after local treatments, such as surgery or radiation
  • helps prevent local/systemic recurrence and improves overall pt. survival
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7
Q

What are Tissue Growth Fraction/Rate and why are they important to consider when providing chemotherapeutic agents?

A

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
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8
Q

What is the Log Cell Kill Hypothesis? How should therapy be given to prevent excessive damage to patients healthy cells?

A
  • 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
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9
Q

What type of infusion is better suited for cell cycle nonspecific vs cell cycle specific antineoplastics?

A

Nonspecific –> intermittent high dose therapy

Specific –> continuous infusion (has practical limitations), also drugs with high metabolism or excretion

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10
Q

What are Pharmacological Sanctuaries and how can they be dealt with?

A
  • 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
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11
Q

How many cycles of treatment do most curable tumors require?

A

6-8 cycles of therapy

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12
Q

Inherent chemotherapeutic resistance vs Acquired chemotherapeutic resistance

A

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

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13
Q

Multidrug Resistance and p-Glycoprotein

bonus: what drug can potentially inhibit it?

A
  • 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)
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14
Q

What are 5 common adverse effects that occur with nearly all CLASSIC antineoplastic agents?

A

nausea, vomiting, fatigue, somatitis (mouth swelling/sores), alopecia (hair loss)

  • also see myelosuppression, low sperm counts, depressed development in children
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15
Q

What are 3 things that can help decrease the effects of myelosuppression, nausea/vomiting, and skeletal complications?

A

Hematopoietic agents - myelosuppression

Serotonin receptor antagonist - nausea/vomiting

Biphosphonates - delay skeletal complications

REST AND RECOVERY

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16
Q

What are 6 common Alkylating agents (CCBPDC) and what is their MOA?

A

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
17
Q

Activation of cyclophosphamide and potential toxicity

What drug can help prevent toxic effects?

A
  • 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
18
Q

What are pharmacological effects of Alkylating Agent usage and what are specific toxicities caused by cyclophosphamide, cisplatin, and busulfan?

A
  • 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

19
Q

What are common Antimetabolites (MFM) and what is their MOA?

A
  • methotrexate, 5-Fluorouracil, 6-Mercaptopurine
  • structural analogs necessary for cell proliferation
  • block/subvert pathways involved in cell replication (CELL CYCLE SPECIFIC for S-PHASE)
20
Q

How does Methotrexate work and why is Leucovorin usually given with it?

A
  • 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)
21
Q

How does 5-Fluorouracil work? (3 active components)

A
  • 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
22
Q

How does Mercaptopurine (6-MP) work? How does Allopurinol effect it?

A
  • 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)
23
Q

What are pharmacological effects of antimetabolites?

A
  • S-phase specific, but otherwise relative little acute toxicity after initial dose
  • common toxicities
24
Q

What common natural antineoplastic drugs? (VVPEDBL-A)

A

vinblastine, vincristine, paclitaxel, etoposide, doxorubicin, bleomycin, L-Asparaginase

25
Q

What is the MOA of Vinca Alkaloids and what are common toxicities of drug use?

A
  • 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
26
Q

What is the MOA of Taxanes and what are common toxicities of drug use?

What cancer are they a traditional treatment for?

A
  • 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

27
Q

What drugs are usefully Topoisomerase I and Topoisomerase II inhibitors? What is the cell cycle specificity?

A

T1: camptothecins (topotecan, irinotecan)
T2: epipodophyllotoxins and anthracycline antibiotics
- etoposide and doxorubicin

S-Phase specific (also G1/G2)

28
Q

What strain of microbe produces all of the anticancer antibiotics currently in use?

A

Streptomyces

  • most mainly affect DNA
29
Q

What is the affect of Antracyclines, Bleomycin, and Dacintomycin on tumors?

What are possible side effects of using these drugs?

A

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

30
Q

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?

A

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

31
Q

Tretinoin and t(15;17)

A
  • 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
32
Q

Imatinib and t(9;22)

A
  • 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
33
Q

What are Erlotinib and Geritinib used to treat and how?

A
  • 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
34
Q

What are the effects of Interferons (Interferon-a2a and a2b) and Interleukin-2 on tumor growth?

A
  • 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

35
Q

Rituximab:

What is its MOA, what is it used to treat, and what are adverse effects of use?

A

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
36
Q

Zif-aflibercept

A
  • 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
37
Q

Malignant Melanoma treatments (5)

A

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

SBL (Skin, Blood, Lymph) Exam 1 and 2 (22 decks)

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