Lecture 12: Cancer Pharm Flashcards Preview

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Flashcards in Lecture 12: Cancer Pharm Deck (37)
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1

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

2

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

3

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

4

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

5

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

6

What is Adjuvent Chemotherapy?

- chemotherapy after local treatments, such as surgery or radiation

- helps prevent local/systemic recurrence and improves overall pt. survival

7

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

8

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

9

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

10

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

11

How many cycles of treatment do most curable tumors require?

6-8 cycles of therapy

12

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

13

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)

14

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

15

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**

16

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

17

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

18

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

19

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)

20

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)

21

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

22

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)

23

What are pharmacological effects of antimetabolites?

- S-phase specific, but otherwise relative little acute toxicity after initial dose

- common toxicities

24

What common natural antineoplastic drugs? (VVPEDBL-A)

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

25

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

26

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**

27

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)

28

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

Streptomyces

- most mainly affect DNA

29

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

30

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**