BIOCHEMICAL COMPONENTS

Targeted therapies

What are molecules, proteins, or chemicals that can attack proliferative and metabolic pathways found only in malignant cells or identify unique signatures of malignant cells and call on the immune system to destroy these cells?

Proteins

What type of molecules are targeted by targeted therapy because they are required for cancer growth?

EGFR (epidermal growth factor receptor)

What is the receptor targeted by inhibitors for cancers exhibiting sustained proliferative signaling?

cyclin-dependent kinase 4 and 6 (CDK4/6)

What are the cell-cycle regulating enzymes inhibited by agents to evade growth suppressors?

VEGF (vascular endothelial growth factor)

What growth factor is targeted by inhibitors to block angiogenesis?

PD-1 and PD-L1

What are the two immune checkpoint molecules/receptors targeted by inhibitors to sensitize T cells to kill cancer cells?

CTLA-4

What immune checkpoint target is manipulated by therapeutic strategies to sensitize T cells to kill cancer cells?

PARP

What enzyme family is targeted by inhibitors in BRCA-mutant cancers to exploit DNA damage pathways?

Tyrosine kinases

What enzyme family activates or phosphorylates pathways needed for proliferation, differentiation, and evasion of apoptosis?

BCR-ABL

What enzyme pathway is targeted by Imatinib, Dasatinib, and Nilotinib?

CD33

What receptor is found on the surface of malignant leukemia cells and targeted by gemtuzumab?

Complement

What protein system is activated by monoclonal antibodies attached to tumor cell receptors, causing destruction via the membrane attack complex?

Fc receptors

What receptors are found on macrophages that bind to monoclonal antibodies attached to tumor cells, initiating phagocytosis?

granzymes

What molecules are secreted by natural killer cells to try to kill off tumor cells after being called upon by monoclonal antibodies?

Growth factors

What molecules found in the cell environment attach to EGFR, leading to dimerization and activation of signaling pathways?

VEGF receptors

What receptors are found on the surface of tumor cells where ligands like VEGFA and VEGFC attach, promoting downstream proliferation?

Programmed Cell Death Protein 1 (PD-1)

What receptors are found on T cells that, when bound by PD-L1, lead to T cell inactivation?

ABL, KIT, or PDGFR

What three receptors are targets for blocking strategies to control malignancies by preventing pathway activation?

FLT3 (FMS-like tyrosine kinase 3)

What mutated receptor/enzyme is targeted by Midostaurin and Gilteritinib in acute myeloid leukemia?

BRAF

What kinase mutation is targeted by Vemurafenib and Dabrafenib in melanoma?

PI3K

What enzyme is targeted by Duvelisib and Idelalisib in chronic lymphocytic leukemia?

JAK1 and JAK2 STAT pathway

What proliferative pathways are inhibited by Ruxolitinib for myeloproliferative neoplasms?

cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6)

What kinases are targeted by Ribociclib and palbociclib in hormone receptor-positive, HER2-negative breast cancer?

Bruton's Tyrosine Kinases (BTK)

What kinases are targeted by Zanubrutinib and ibrutinib for various lymphomas and macroglobulinemia?

PARP1, PARP2, and PARP3

What enzymes are targeted by Olaparib in cancers such as ovarian and breast cancer?

DNMT (DNA methyltransferase)

What enzyme is targeted by Azacitidine and Decitabine for myelodysplastic syndromes and acute myeloid leukemia?

HDAC (histone deacetylase)

What enzyme is targeted by Vorinostat, Belinostat, and Panobinostat in various lymphomas and multiple myeloma?

XPO1 (nuclear exporter 1)

What protein is targeted by Selinexor in multiple myeloma and diffuse large B-cell lymphoma?

mTOR (mammalian target of rapamycin)

What enzyme/complex is inhibited by Temsirolimus and Everolimus in malignancies like renal cell carcinoma?

Testosterone

What chemical is converted to dihydrotestosterone (DHT) which activates androgen receptors in prostate cancer?

dihydrotestosterone (DHT)

What molecule activates androgen receptors, leading to cellular proliferation and evasion of apoptosis in prostate cancer?

Estradiol (Estrogen)

What hormone activates estrogen receptors in breast cancer, leading to gene transcription promoting proliferation?

androstenedione or testosterone

What androgens are converted to estradiol in peripheral fat (and estrone)?

estrone

What molecule, derived from testosterone or androstenedione, is a source for estradiol?

Aromatase

What enzyme is responsible for converting androstenedione to estrone?

5-Alpha Reductase

What enzyme is inhibited to prevent the conversion of testosterone to dihydrotestosterone (DHT)?

LHRH (GnRH)

What hormone axis do agonists manipulate to stop the pituitary from secreting luteinizing hormone?

luteinizing hormone

What hormone's secretion is stopped by LHRH/GnRH agonists acting through the pituitary gland?

ALL TRANS-RETINOIC ACID (ATRA) (Vitamin A derivative)

What chemical is used in differentiation therapy for acute promyelocytic leukemia, allowing maturation into granulocytes?

VEGF (Vascular Endothelial Growth Factor)

What ligand/growth factor's binding to VEGFR is inhibited by Bevacizumab?

Alkylating Agents

What class of chemotherapy drugs stick to or stop DNA synthesis, destroying the actual DNA?

DNA bases

What substances do alkylating agents bind to in order to halt DNA replication?

Antimetabolites

What class of chemotherapy reagents relate to folic acid synthesis and mimic purines and pyrimidines?

Purines (Adenine, Guanine) and Pyrimidines (Cytosine, Thymine, Uracil)

What DNA bases are mimicked by antimetabolites?

Acrolein

What metabolite causes hemorrhagic cystitis by releasing inflammatory mediators?

hydrogen peroxide (oxygen-free radical)

What chemical compound is formed by Procarbazine and Dacarbazine, generating free radicals that cause DNA strand scission?

dihydrofolate reductase

What enzyme is inhibited by Methotrexate, decreasing the synthesis of purine nucleotides and amino acids?

p-Aminobenzoic acid (PABA)

What substance is converted to dihydrofolic acid via Dihydropteroate synthase, and is competitively mimicked by sulfonamides?

hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

What enzyme activates the antimetabolite 6-Mercaptopurine?

xanthine oxidase

What enzyme converts purine to uric acid and is inhibited by allopurinol and febuxostat?

thymidylate synthase

What enzyme is inhibited by 5-Fluorouracil, leading to thymineless death of cells?

ribonucleotide reductase

What enzyme is inhibited by Cytarabine and Gemcitabine, reducing the formation of dNTPs and inhibiting DNA synthesis and repair?

microtubules

What cellular structures are prevented from assembling by Vincristine and Vinblastine, causing cell arrest at metaphase?

DNA topoisomerase II (DNA gyrase)

What enzyme, inhibited by Etoposide, removes supercoiling of DNA?

DNA topoisomerase I

What enzyme is inhibited by Topotecan and Irinotecan?

Asparaginase

What substrate-depleting enzyme is used to treat acute lymphoblastic leukemia by depleting serum asparagine?

asparagine

What important amino acid for cancer cell growth is depleted by Asparaginase?

Hemoglobin

What protein molecule carries oxygen and is composed of heme (protoporphyrin ring) and globin (protein)?

Iron

What element is found in the middle of globin chains together with the heme part of hemoglobin where oxygen is stored?

Myoglobin

What protein is found in muscle tissue, responsible for the red color, and contains iron?

ferritin

What protein serves as the storage form of iron (10-20% of total body iron)?

H+ proton

What compound/element needs to be present (acidic environment) for the absorption of ferrous iron in the duodenum?

heme carrier protein 1 (HCP1)

What protein allows heme-bound iron to enter the enterocyte from the duodenal lumen?

duodenal cytochrome B (dcytb)

What enzyme converts free (nonheme) iron (Fe3+) to its Fe2+ (ferrous) form for absorption?

divalent metal transporter 1 (DMT1)

What protein co-transports Fe2+ (ferrous) iron and H+ proton into the enterocyte?

ferroportin

What protein allows Fe2+ (ferrous) iron to exit the duodenal cell?

hephaestin

What enzyme/protein converts Fe2+ (ferrous) iron to Fe3+ (ferric) iron form upon exiting the enterocyte?

transferrin

What protein transports Fe3+ (ferric) iron through the blood to wherever it is needed?

iron chelators (Desferrioxamine, Deferiprone, Deferasirox)

What compounds scavenge excess iron by attaching to it to be excreted in the urine?

Folate

What molecule is needed for DNA synthesis and red cell maturation?

Vitamin B12 (Cobalamin)

What molecule scavenges the methyl group from tetrahydrofolate?

N5-Methyltetrahydrofolate (MTHF)

What dietary folate compound enters the body and loses its methyl group to Cobalamin?

Tetrahydrofolate

What molecule enters the folate cycle to produce purines and thymidine after being converted from MTHF?

Intrinsic factor (IF)

What protein is produced by parietal cells in the stomach and is needed for Vitamin B12 absorption in the terminal ileum?

Epoetin (recombinant product)

What synthetic molecule interacts with erythroid receptors on red cell progenitors to increase red cell mass?

erythropoietin

What hormone naturally made in the kidneys, if deficient, manifests as anemia in chronic kidney disease patients?

Granulocyte-colony stimulating factor (G-CSF) and Granulocyte-macrophage colony stimulating factors (GM-CSF)

What cytokines/growth factors stimulate proliferation and differentiation via receptors on myeloid cells, increasing neutrophil count?

Thrombopoietin

What growth factor stimulates the production and proliferation of platelets?

IL-11 (Interleukin 11)

What thrombopoietic growth factor is given in recombinant form to enhance megakaryocyte maturation?

Mpl receptors

What receptors are activated by Thrombopoietin and TPOR mimetics to stimulate megakaryopoiesis?

plasmepsin I/II falcipain

What enzymes metabolize hemoglobin into toxic heme and globin?

heme

What toxic product of hemoglobin metabolism must be detoxified by the Plasmodium parasite?

hemozoin

What non-toxic malarial pigment is crystallized from heme during detoxification?

carbon-centered free radicals

What compounds are formed by the cleavage of artemisinin by iron, leading to alkylation of multiple proteins to kill the parasite?

iron

What element activates or cleaves artemisinin?

cysteine proteases

What enzymes involved in hemoglobin digestion are disabled by artemisinin alkylation?

PfATP6 (ATPase)

What enzyme/protein ensures normal intracellular Ca2+ levels in RBCs, and whose disruption by artemisinin triggers parasite death?

heme-quinoline complex

What compound is formed when quinolines bind to heme, blocking its detoxification and causing toxicity/accumulation?

Dihydrofolate reductase (DHFR) and Dihydropteroate synthase (DHPS)

What two enzymes are needed for folic acid synthesis and are targeted by inhibitors in Plasmodium?

apicoplast

What structure's formation is blocked by Doxycycline, impairing the Plasmodium parasite's invasion into the target cell?

50S ribosome

What ribosomal subunit is blocked by Clindamycin to inhibit protein synthesis in Plasmodium?

Ubiquinone

What compound is mimicked by Atovaquone, leading to the collapse of the mitochondrial complex and blocked ATP synthesis in Plasmodium?

Amphotericin B

What polyene macrolide binds to ergosterol in the fungal plasma membrane, forming pores to cause cell leakage?

ergosterol

What sterol molecule is contained in the rigid cell wall and cell membrane of fungi and is targeted by polyenes?

fungal ergosterol and human cholesterol

Amphotericin B preferentially binds to what two sterol molecules, exhibiting less toxicity by choosing the fungal one?

cytosine permease

What enzyme is found in fungal cells (not mammalian cells) that allows 5-FC entry?

cytosine deaminase

What enzyme converts 5-FC to 5-fluorouracil (5-FU) and is absent in mammalian cells?

5-fluorouracil (5-FU)

What toxic antineoplastic metabolite of 5-FC inhibits fungal DNA and RNA synthesis?

lanosterol 14 alpha-demethylase (c-14 alpha-demethylase)

What fungal cytochrome P450 enzyme is inhibited by Azoles, blocking ergosterol synthesis?

glucans

What component in the fungal cell wall, inhibited by Echinocandins, leads to cell lysis?