3. Cancer Pharmacology Part 1

Question 1

What are genes that positively influence tumor formation such as RAS?

Answer 1

Oncogenes (overexpression)

Question 2

What are genes that negatively impact tumor growth such as p53?

Answer 2

Tumor Suppressors (supression/knock out)

Question 3

Cell Cycle Review First to Last
Mitotic Phase (Cell division) = M phase
Gap Phase 1= G1
Resting Phase= G0
Synthetic Phase = S Phase = DNA replication
Gap Phase 2= G2 (end - back to M phase)
G1 and G2 STOP inappropriate cell cycle progression via check points- either end in cell cycle arrest or entry into G0. Activation of oncogenes overrides (GF/RAS) which checkpoint and Inactivation of tumor suppressor genes (p53) overrides which checkpoint?

Answer 3

Activation of oncogenes overrides G1 arrest (restriction point to check mitotic division errors)
Inactivation of tumor suppressor genes overrides G2 (DNA replication checkpoint)

Question 4

What is chemotherapy that is administered usually in advanced cancer with no alt. treatments or in advanced metastatic disease with goals of relieving tumor sx, improve quality of life and prolong time to tumor progression?

Answer 4

Primary Chemotherapy

Question 5

What type of chemotherapy is used in patients who present with localized cancer for which alternative local therapies like surgery exist but which have been shown to be less than completely effective, given before surgery to shrink tumor?

Answer 5

Neoadjuvant Chemotherapy

Question 6

What type of chemotherapy is used as an adjuvant to local therapy and administered after surgery to reduced incidence of local and systemic recurrence and improve overall survival of patients, prolonging disease free survival?

Answer 6

Adjuvant Chemotherapy

Question 7

What type of chemotherapeutic resistance occurs as drug resistance in the absence of prior exposure to available standard agents, or d/t genomic instability of cancer such as p53 mutations?

Answer 7

Primary/Inherent Chemotherapeutic Resistance

Question 8

What type of chemo resistance develops in response to exposure to a given cancer chemotherapeutic drug, or due to genetic change such as amplification or suppression of a particular gene?

Answer 8

Acquired Chemotherapeutic Drug Resistance

Question 9

p-Glycoprotein- PGP (MDR1) expression is in tissues with barrier functions including kidney, liver, GI tract, they have pharmacological barrier sites at BBB and placenta blood barrier, high baseline expression of PGP correlates with primary/inherent resistance to natural products, and or can be overexpressed leading to acquired?

Answer 9

Drug resistance

Question 10

Chemotherapy has limited selective toxicity kind of like a bull in a china shop- kills tumor and human cells without specificity. Therapeutic index is Toxic dose50/effective dose 50, chemo drugs have LOW therapeutic index which means small difference between effective and toxic doses, what doses are required to maximize cancer cell death?

Answer 10

HIGH doses are required to maximize rapid cancer cell death***

Question 11

Normal cells are susceptible to adverse effects of chemotherapy such as bone marrow precurosors of blood cells causing myelosuppression and cytopenias, intestinal epithelial cells, oral mucosa, gondal cells (testes/ovaries), and what on the skin?

Answer 11

Hair follicles leading to alopecia

Question 12

Alkylating agents transfer an alkyl groups (CH-CH3-CH3) to DNA leading to DNA cross linking, arrest occurs in late G1/ Sphase*, individual drugs vary in how they do this (cisplatin vs cyclophosphamide), what cells are the most susceptible?

Answer 12

Replicating cells** no effect on older-senscent cells

Question 13

Some mechanisms of resistance to alkylating agents include decreased cellular transport of the drug (influx/efflux), increased expression of activity of glutathione and glutathione proteins (inactivates it), and increased capability to repair DNA lesions through increased expression and activity of DNA repair genes such as?

Answer 13

MGMT (O-methylguanine-DNA methyltransferase)

Question 14

Side effects of alkylating agents primarily occur in rapidly growing tissue- including myelosuppression, GI tract- diarrhea, repro system, N/V, blistering at site of admin, and increased risk of secondary malignancies** such as?

Answer 14

Acute Myelogenous leukemia AML

Question 15

Resistance to bis(chloroethyl) amines including cyclophosphamide mechlorethamine, melphalan and chlorambucil occurs via inc. expression of DNA repair enzymes MGMT, and inc. expression of glutathione, what agent is HIGHLY lipophilic which allows it to cross the BBB to treat glioblastomas?

Answer 15

Carmustine

Question 16

What cancer agent mimics and or reduces the essential components needed for the formation of DNA, RNA, and proteins, arrest and or DNA damage occuring during S phase, replicating cells are the most susceptible?

Answer 16

Antimetabolites (MTX/cytarabine)

Question 17

MOR for antimetabolites include inhibition of metabolism into active metabolites such as cytarabine and its active metabolity Ara-CTP, decreased drug transport, and decreased formation of poly glutamate metabolites by folyl polyglutamate synthase FPGS- important for pemetrexed, pralatrexate and?

Answer 17

Methotrexate

Question 18

Adverse effects of antimetabolites include myelosuppression, N/V, diarrhea/mucositis (esp 5FU), hand foot syndrome which is painful erythema and swelling of the hands and feet (premetrexed), what is used as a ‘rescue’ for MTX toxicity?

Answer 18

Leucovorin (folinic acid)

Question 19

What antimetabolite is the single most active agent for acute myelogenous leukemia AML, is a deoxycytidine analog converted to triphosphate metabolite (ara-CTP) which competitively binds DNA polymerase A (block DNA synthesis) and DNA polymerase B (blocks DNA repair), and it also is incorporated into DNA, interfereing with chain elongation and is incorporated into RNA?

Answer 19

Cytarabine - Antimetabolite

Question 20

What antimetabolite is a purine antagonist inactive in parent form (azathioprine), metabolized by HGPRT to form monophosphate nucleotide 6-thioinosinic acid, which inhibits several enzymes of de novo purine nucleotide synthesis, triphosphate form is incorporated into RNA and DNA?

Answer 20

6-Mercaptopurine (6-MP)- purine antagonist

Question 21

What class of cancer agents consists of tubulin polymerization inhibition (vinblastine/cristine/vinorelbine) and activation (paclitaxel***, docetaxel, cabazitaxel) and topoisomerase inhibitors (type 1 = topotecan/irinotecan, Type 2= etoposide)?

Answer 21

Natural products

Question 22

Natural products have mechanisms of resistance that include point mutations in drug binding pockets (topoisomerase 1/2) and what mediated drug efflux?

Answer 22

p-glycoprotein PGP

Question 23

Adverse effects of natural products (tubulin polymerization inhib/enhance and topoisomerase 1/2 inhib) include myelosuppression, N/V, hypersensitivity (allergic reaction) seen with paclitaxel and docetaxel, diarrhea assoc with topotecan and irnotecan and neurotoxicity MC with?

Answer 23

Vincrisitine (glove and stocking neuropathy)

Question 24

Paclitaxel (taxane natural product) enhances tubulin polymerization, Vinblastine (vinca alkaloid natrual product) inhibits tubulin polymerase distrupting assembly of microtubules, p-glycoprotein expression often confers resistance to natural products, besides which agent which avoids the MOR?

Answer 24

Cabazitaxel (taxane)

Question 25

What class of chemo agents includes inhibition of topoisomerase 2, generation of free radicals (DNA damage), DNA intercalation (all by anthracyclines), induce DNA cross links (mitomycin) and causes DNA fragmentation and single/double strand breaks due to free radicals (bleomycin)?

Answer 25

Antitumor antibiotics

Question 26

Antitumor antibiotics MOR includes point mutations in topoisomerase 2 allowing suppression of apoptotic signaling (doxorubicin), increased expression of efflux pumps (pgp) (doxorubicin/mitomycin), and upregulation of what which inhibits bleomycin iron binding and limits its effects?

Answer 26

Upregulation of bleomycin hydrolase enzyme

Question 27

Adverse effects of Antitumor antibiotics include myelosuppression, N/V, blue discoloration of the fingernails, sclera, and urine due to mitoxantrone, pulmonary toxicity due to bleomycin, and free radical mediated cardiotoxicity due to?*** test q

Answer 27

Doxorubicin

Question 28

Doxorubicin induced cardiotoxicity - acute form in first 2-3 days- arrhythmias and conduction abnls, pericarditis, myocarditis, transient and asx, chronic form: dose dependent- dilated cardiomyopathy HF, inc production of oxygen free radicals eithin the myocardium, and to avoid this SE you can either lower weekly doses or do continuous?

Answer 28

continuous infusion which reduces the likelihood

Question 29

Tyrosine kinase and GF receptor inhibitors have a MOR of point mutations in drug binding sites, with common SE being N/V, and acneform skin rash and hypersensitivity MC seen with what -mab?

Answer 29

Cetuximab

Question 30

What tyrosine kinase inhibitor is an inhibitor of Bcr-Abl oncoprotein, and is the standard first line tx in untreated patients with CML - philadelphia chromosomal translocation t9:22?

Answer 30

Imatinib

Question 31

What is a recombinant fusion protein made up of portions of the extracellular domains of human VEGF receptors 1 and 2 fused to Fc portion of the human IgG1 molecule, soluble receptor to VEGFA/B and placental growth factor PIGF, binding of VEGF ligands prevents their interactions with VEGFR leading to an inhibition of signaling?

Answer 31

Ziv-aflibercept

Question 32

There are two types of Immune checkpoint inhibitors, including PD-1 inhibitors such as Nivolumab and Pembrolizumab which are used in MM, NSCLC, and Hodgkins Lymphoma, and what inhibitors such as Atezolizumab, Avelumab, Durvalumab which are used in bladder cancer, NSCLC, and merkel cell skin cancer?

Answer 32

PDL1-Inhibitors

“release brakes of the immune system”

Question 33

Immune checkpoint inhibitors work via the following: T cells are activated by dendritic cells within the LN, activated T cell penetrates the tumor microenvironment which includes tumor cells, Mø and T reg cells, the tumor possess PDL1- activated T cells may induce PDL1 upregulation on tumor cells mø and Treg cells via interferon-gamma, what occurs when a T cell binds PDL1 on a tumor?

Answer 33

the T-cell inactivates = tumor LIVES

B7.1 and PD1 are receptors on T cells for PDL1

Question 34

Immune checkpoint inhibitors have a MOR including primary or acquired, insufficient generation of anti-tumor T cells, inadequate function of tumor specific T cells, impaired formation of T cell memory. Common SE include fatigue, nausea, loss appetite, itching and can allow the immune system to attack normal organs*** serious- such as?4

Answer 34

lungs
intestines
liver
kidneys