Chapter 8 anticancer - miscellaneous cancer drugs

Question 1

vorinostat (zolinza)
belinostat (belqodaq)
romidepsin (istodax)
panobinostat (farydak)

misc

Answer 1

• DNA is wrapped around histone (some cancers happen or are supported for abnormal expression due to these two structures interacting)
• Histone deacetylase (HDAC) inhibitors prevent HDACs from deacetylating histones => they cahnge the expression level of many genes (SOME integral to cancer growth)

Question 2

bortezomib (velcade)
carfilzomib (kyprolis)

misc

Answer 2

protesome inhibitors
* proteins degraded inside cells by complexes of proteases in structure called proteasome
* protein production + degradation => cellular homeostasis (especially for cancer)
* these inhibitors disrupt this process for cancer cells

indication
* lymphoma and multiple myeloma (blood cancer that develops in plasma cells in the bone marrow—the soft, spongy tissue at the center of your bones — cancerous plasma cells accumulate in the bone marrow and crowd out healthy blood cells; unable to fight off infection)
* NOT FOR SOLID TUMORS

IV injection

Question 3

arsenic trioxide (trisenox)

misc

Answer 3

• degrades PML-retinoic acid receptor (fusion protein) —- involved in acute promyelocytic leukemia (blood cancer characterized by a marked increase in a type of immature white blood cells known as promyelocytes.)
• interfere w/ other cellular signaling pathways and cause apoptosis in number of cancer cell types in vitro => glass lab

Question 4

niraparib (zejula)
olaparib (lynparza)
rucaparib (rubraca)
talazoparib (talzenna)

misc

Answer 4

• Poly (ADP ribose) polymerse or PARP inhibitors
• PARP — cell growth and survival
• another gene + protein that helps with cancer cell survival is BRCA (breast cancer for e.g w/ BRCA mutations) — PARP is the only remaining mech to keep those cells alive!

Question 5

venetoclax (venclexta)

misc

Answer 5

BCL-2 inhibitors
* BCL-2 (antiapoptotic protein that prevent cancer cells from dying even after being tx’d with chemo

Indication
* process w/ alot of BCL-2 expression such as CLL or chronic lymphocytic leukemia

Question 6

Palbociclib (ibrance)
Ribociclib (kisquali)
abemaciclib (verzenio)

misc

Answer 6

• CDK4/6 inhibitors (cyclin dependent kinases 4 + 6)
• active in G1-S phase of the cell cycle
• when inhibited, there is no phosphorylation of RB1 (retinoblastoma protein family) l/t release of transcription factor E2F, which activates transcription of genes that drive progess thorugh G1/S phase
• OVERALL —- blocks cell cycle progression

Question 7

Ivosidenib (tibsovo)

misc

Answer 7

IDH1 inhibitor (isocitrate dehydrogenease)
* cytoplasmic enzyme that yields a-ketoglutarate (from isocitrate)
* Mutated IDH1 drives abnormal 2-HG production (2-hydroxygluuarate), which then inhbits histone and DNA demethylases (inactive) causing altered gene expression and drives cancers

Question 8

enasidenib (idhifa)

misc

Answer 8

• isocitrate dehydrogenase - 2 (IDH2) inhibitors
• a mitochondrial enzyme that metabolzied NADP (+) ===> mutated in acute myelogenous leukemia (AML) — a cancer of the blood and bone marrow. It is the most common type of acute leukemia in adults. This type of cancer usually gets worse quickly if it is not treated.
• this drug is approved for AML

effects
* differentiation syndrome (potentially fatal complication of treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid and/or arsenic trioxide, treatment of acute myeloid leukemia (AML) with inhibitors of isocitrate dehydrogenase )
1) acute resp distress
2) hypoxia
3) liver or kidney impairment
4) pleural effusions (buildup of fluid between the layers of tissue that line the lungs and chest cavity.)
5) fever
6) edema
* reduced bood count

Question 9

Vismodegib (erivedge)
Sonidegib (odomzo)
Glasdegib (daurismo)

misc

Answer 9

• shh pathway inhibitor (Sonic hedgehog)
• blocks activity of smoothened protein + reduce shh activity
• indicated for manly cancers driven by shh pathway driven cancers (basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers of the breast, lung, pancreas, and prostate for e.g.)

effects
* may cause severe birth defects
* if used by pregnant individual — shh pathway is critical for embryo development

Question 10

asparaginase (erwinaze, asparlas)

misc

Answer 10

• hydrolyze l-asparagine to aspartate
• lack of asparagines DESTROYS tumors cells that lack asparagine synthethase
  /////
• not phase specific
• normal cells… do synthesize asparagine

Question 11

hydroxyurea

misc

Answer 11

• s -phase specific
• inhibits ribonucleotide reductases
• including deoxyribonucleotide synthesis
• e.g. — deoxyribonucleotides are: dAMP, dCMP, dUMP, dGMP, dTMP

indication
* chronic granulocytic leukemia

effects
* marrow suppression

Question 12

mitotane

misc

Answer 12

• isomer of DDT (pesticide now banned)
• kills adrenocortical cells (outer layer of the adrenal gland. )

indication
* palliative tx of adrenocortical carinoma

stored in fat and slowly released

effects
* GI distress
* lethargy
* weakness
* dizziness

Question 13

tretinoin (vesanoid)
isotretinoin (accutane)

misc

Answer 13

• analog of retinoic acid (vitamin A) that induces maturation in
  1) acute promyelocytic leukemia cells (large atypical promyelocytes and other myeloid precursors in various stages of development in the peripheral blood. The bone marrow is hypercellular, and APL promyelocytes account for about 30% of the myeloid cells in the classic variant)
  2) neuroblastoma (cancers that start in early nerve cells (called neuroblasts) of the sympathetic nervous system, so they can be found anywhere along this system. Most neuroblastomas begin in the abdomen, either in an adrenal gland or in sympathetic nerve ganglia.)
• disrupt growth - overall

effects
* retinoic acid-syndrome
1) fever
2) dyspnea
3) pulmonary infiltrates (substance denser than air, such as pus, blood, or protein, which lingers within the parenchyma of the lungs. ) and effusions
4) fluid retention
* transient leukocytosis (inc level of leukocytes)
* pseudotumor cerebri - false brain tumor.” It is likely due to high pressure within the skull caused by the buildup or poor absorption of cerebrospinal fluid (CSF).

Question 13

bexarotene (targretin)

misc

Answer 13

• selectively binds and activates retinoid X receptor subtypes (RXR, a+b+y)
• they act as transcription factors that regular gene expresion that encodes proteins (cellular diff and proliferation)

indication
* refractory cutaneous t-cell lymphoma (not responding to tx or eventually stopped)

risk
* birth defects

Question 14

porfimer (photofrin)

misc

Answer 14

• photosensitizing porphryin (essential for aerobic life, because of their key role in processes related to oxygen production, oxygen transport, and oxygen use) tha is toxic to cancers exposed to 630 nm light
• preferred to be retained in cancers after clearing of much of normal cells
• light exposure induces excited state which spin transfer to o2 to form toxic o2 free radicals!

indication
* palliation of esophageal cancers that occlude airway