W10: Cancer Treatment

Alkylating agents

MOA - Cross-link DNA, RNA, proteins, Strong electrophiles (e.g. C+ ions) react with e- rich nucleophilic moieties on DNA to inhibit cell division & proliferation

MRM - ↑ DNA repair, ↓ drug uptake, ↑ drug inactivation

AE - Any organ in the body which has rapidly dividing stem cells, off site toxicity can occur:

Bone marrow toxicity & leukemogenic

Mucosal toxicity (oral & G.I.) & genitourinary tract

Alopecia (hair loss)

Neurotoxicity

Hepatotoxicity & hepatic veno-occlusive disease (vascular endothelial damage)

Renal toxicity

Reproductive & developmental toxicity

G - Can occur in any cell cycle stage

Nitrogen mustards

D - Alkylating agent

D - Cancer

MOA - Unstable and react with themselves to form activated electrophilic cations.

Nucleophiles in our biomolecules attack the electrophile to form DNA adducts.

These inhibit cell division and proliferation.

MRM - ↑ DNA repair, ↓ drug uptake, ↑ drug inactivation

AE - Any organ in the body which has rapidly dividing stem cells, off site toxicity can occur:

Bone marrow toxicity & leukemogenic

Mucosal toxicity (oral & G.I.) & genitourinary tract

Alopecia (hair loss)

Neurotoxicity

Hepatotoxicity & hepatic veno-occlusive disease (vascular endothelial damage)

Renal toxicity

Reproductive & developmental toxicity

G - Can occur in any cell cycle stage

Antimetabolites

MOA - Inhibit DNA formation or polymerisation

They are chemical analogs of DNA & RNA building blocks

Disrupt nucleotide synthesis, utilization, incorporation

Inhibits ribonucleotide reductase (hydroxyurea; blocks R to dR)

MRM - ↓ drug uptake, ↓ drug activation, ↑ drug inactivation, ↑ or altered target enzyme, salvage pathway

DLT - Bone marrow (myelosuppression)

AE - Cardiovascular (CV), G.I.T.,

hepatotoxicity, infection, neurotoxicity, nephrotoxicity

G - targets S phase

Methotrexate

D - Antimetabolite

D - Pyrimidine synthesis inhibitor

MOA - Interferes the conversion of dihydrofolate to tetrahydrofolate, disrupting DNA synthesis

MRM - ↓ drug uptake, ↓ drug activation, ↑ drug inactivation, ↑ or altered target enzyme, salvage pathway

DLT - Bone marrow (myelosuppression)

AE - Cardiovascular (CV), G.I.T.,

hepatotoxicity, infection, neurotoxicity, nephrotoxicity

G - targets S phase

5-Fluorouracil (uracil analog), Floxuridine

D - Antimetabolite

D - Pyrimidine synthesis inhibitor

MOA - Interferes with the ribonucleotide to the deoxyribonucleotide inhibiting thymidylate synthase

MRM - ↓ drug uptake, ↓ drug activation, ↑ drug inactivation, ↑ or altered target enzyme, salvage pathway

DLT - Bone marrow (myelosuppression)

AE - Cardiovascular (CV), G.I.T.,

hepatotoxicity, infection, neurotoxicity, nephrotoxicity

G - targets S phase

Cytarabine (cytidine analog), Gemcitabine

D - Antimetabolite

D - Pyrimidine synthesis inhibitor

MOA - Stops DNA formation by acting as a false nucleotide during synthesis, cannot be read as it is not cytidine

MRM - ↓ drug uptake, ↓ drug activation, ↑ drug inactivation, ↑ or altered target enzyme, salvage pathway

DLT - Bone marrow (myelosuppression)

AE - Cardiovascular (CV), G.I.T.,

hepatotoxicity, infection, neurotoxicity, nephrotoxicity

G - targets S phase

Hydroxyurea

D - Antimetabolite

D - Pyrimidine synthesis + purine synthesis inhibitor

MOA - Inhibits ribonucleoside diphosphate reductase interfering DNA synthesis

MRM - ↓ drug uptake, ↓ drug activation, ↑ drug inactivation, ↑ or altered target enzyme, salvage pathway

DLT - Bone marrow (myelosuppression)

AE - Cardiovascular (CV), G.I.T.,

hepatotoxicity, infection, neurotoxicity, nephrotoxicity

G - targets S phase

Mercaptopurine (purine analog)

D - Antimetabolite

D - Purine synthesis inhibitor

MOA - Stops DNA formation by acting as a false nucleotide during synthesis, cannot be read MRM - ↓ drug uptake, ↓ drug activation, ↑ drug inactivation, ↑ or altered target enzyme, salvage pathway

DLT - Bone marrow (myelosuppression)

AE - Cardiovascular (CV), G.I.T.,

hepatotoxicity, infection, neurotoxicity, nephrotoxicity

G - targets S phase

Fludarabine, Cladaribine

D - Antimetabolite

D - Purine synthesis inhibitor

MOA - Stops DNA formation by acting as a false nucleotide during synthesis, cannot be read

MRM - ↓ drug uptake, ↓ drug activation, ↑ drug inactivation, ↑ or altered target enzyme, salvage pathway

DLT - Bone marrow (myelosuppression)

AE - Cardiovascular (CV), G.I.T.,

hepatotoxicity, infection, neurotoxicity, nephrotoxicity

G - targets S phase

Antiestrogen - (tamoxifen)

D: Estrogen dependent anti-cancer drug

D: breast cancers

MOA: selective estrogen receptor modulator (SERM)- acts as a major competitive estrogen receptor antagonist.

MRM: loss of hormonal sensitivity (d/t increased or altered target receptor)

AE: long term use (5+ years) can result in endometrial cell proliferation and cancer.

Androgens - (testosterone, proprionate, fluoxymesterone)

D: Estrogen dependent anti-cancer drug

D: breast cancers

MOA: decrease estrogen by increasing testosterone via feedback loops in anterior pituitary

MRM: loss of hormonal sensitivity (d/t increased or altered target receptor)

AE: ?

Aromatase inhibitors - (Anastrozole, letrozole, exemestane, formestane)

D: Estrogen dependent anti-cancer drug

D: breast cancers

MOA: block action of CYP19 enzyme (converts testosterone into eostrogen), causing increased levels of testosterone and lower levels of estrogen, starving tumour.

MRM: loss of hormonal sensitivity (d/t increased or altered target receptor)

AE: ?

Estrogens - (Diethylstilbestrol (DES), Ethinylestriadiol)

D: Testosterone dependent anti-cancer drug

D: Prostate cancer

MOA: deprive tumour by increasing estrogen levels

MRM: loss of hormonal sensitivity (d/t increased or altered target receptor)

AE: ?

G: not phase specific

Antiadrogen - (Flutamide + Bicalutamide)

D: Testosterone dependent anti-cancer drug

D: Prostate cancer

MOA: block testicular and adrenal androgen production (inhibit receptor translocation to nucleus---stop message being sent to nucleus), decreasing testosterone.

MRM: loss of hormonal sensitivity (d/t increased or altered target receptor)

AE:

G: not phase specific

Antiadrogen - (Finasteride)

D: Testosterone dependent anti-cancer drug

D: Prostate cancer

MOA: Blocks 5a-reductase (converts testosterone into Dihydroteestosterone---most potent form), decreasing testosterone levels.

MRM: loss of hormonal sensitivity (d/t increased or altered target receptor)

AE:

G: not phase specific

Gonadotropin-Releasing Hormone Analog- (Leuprolide)

D: Testosterone dependent anti-cancer drug

D: Prostate cancer

MOA: decreases Estrogen (in women), and testosterone (in men)

MRM: ?

AE: ?

G: often given alongside Flutamide for prostate cancer.

CAN ALSO BE USED TO TREAT ESTROGEN DEPENDENT CANCERS-BREAST CANCER.

Epidermal Growth Factor Receptor tyrosine kinase inhibitor (EGFR TKI)--- Gefitinib Erlotinib

D: Specific tyrosine kinase inhibitor (TKI)

D: lung and pancreatic cancer

MOA: an over expression of EGFR linked to malignancy, these drugs act to inhibit EGFR expression

MRM: ?

AE: Skin, GIT toxicity, fluid retention

G: ?

Platelet Derived Growth Factor Receptor Tyrosine Kinase Inhibitor (PDGFR TKI)---Imatinib, Dosatinib, Nilotinib

D: Specific tyrosine kinase inhibitor (TKI)

D: chronic myeloid leukaemia cells (CML)

MOA: inhibits BCR-ABL enzyme which is vital for tumour survival

MRM: mutations in target gene (e.g. in BCR-ABL)

AE: Skin, GIT toxicity, fluid retention

G: Dosatinib, Nilotinib used to treat Imatinib resistant tumours

Angiostatin

D: Angiogenesis Inhibitor

D: Tumour growth inhibitor

MOA: endogenous inhibitor produced with plasminogen cleavage from matrix metalloproteinases from tumour cells

MRM: ?

AE: Renal (Proteinuria), Hypertension

G: ?

mAbs against VEGF--- Bevacizumab

D: Monoclonal antibody

D: Angiogenesis inhibitor

MOA: inhibits VEGF-A, decreasing the signal for blood vessel growth

MRM: extrinsic/intrinsic mechanisms evading VEGF dependence.

AE: Renal (Proteinuria), Hypertension

G: ?

VEGF receptor TKI--- vandetanib, sunitanib

D: Angiogenesis inhibitor

D: extrinsic/intrinsic mechanisms evading VEGF dependence.

MOA: inhibits VEGF, decreasing the signal for blood vessel growth

MRM: ?

AE: Renal (Proteinuria), Hypertension

G: ?

Thalidomide

D: Angiogenesis inhibitor

D: treats multiple myeloma when used with Dexamethasone.

MOA: used for antiangiogenic and immunomodulatory effect (inhibits TNF-a synthesis, and co-stimulates T-cell production), decreasing blood supply to tumours.

MRM:

AE: teratogenic

G: used alongside Dexamethasone to treat multiple myeloma. The second-generation drug is Lenalidomide.

Rituximab, Alemtozumab

D: mAB, DMARDs

D: Rheumatoid arthritis

MOA: Binds to CD 20 and marks

the B cells for attack by NK cells, reduces autoimmune attack

MRM: ?

AE: ?

G: ?

Doxorubican

D - Anthracyclines (cytotoxic)

D - Used for leukemias, lymphomas, breast

cancer

MOA - Intercalates DNA

- Redox cycles to generate reactive

oxygen species (ROS)

- single strand & double strand breaks

MRM -

AE - Causes cardiotoxicity, alopecia,

myelosuppression

G - Most active in G2 phase

Bleomycin

D - Anthracyclines (cytotoxic)

D -

MOA - Glycopeptide from Streptomyces, binds both Fe2+ and DNA to fragment DNA

• Bleomycin (orange) complexes Fe2+ (red ball) and binds to dsDNA

• Iron-bleomycin complex performs Fenton reaction:

1 e- reduction of O2 to generate O2.

- & other ROS

• These free radicals cause ss

and ds breaks in DNA

MRM -

AE -

G -

D -Plant alkaloids

MOA - Stabilize the intermediate DNA complex with topoisomerase I, enzyme reduces stress in the DNA helix by rapidly making and revealing single strand DNA breaks

MRM -

AE -

G - most active in S phase

Etoposide, teniposide

D - Epipodophyllotoxins

D -

MOA - semi-synthetics based on topoisomerase inhibitors from mandrake roots

• form ternary complexes with topoisomerase II & DNA, causing ds breaks

MRM -

AE -

G - • most active in S & G2 phases

• synergistic (combination) with alkylators (cisplatin) & bleomycin

Topoisomerase II also regulates DNA supercoiling

Vinblastine, vincristine

D - Vinca alkaloid

D -

MOA - "spindle poisons" that bind tubulin to inhibit microtubule formation

- most active in M phase; side effects: Vinblastine, myelosuppression; Vincristine, peripheral neuropathy

Paclitaxel (Taxol):

D - Taxanes:

MOA - antimicrotubule that binds tubulin to promote

its polymerisation to form stable non-functional microtubules halts cells in late G2 & M phases

- inhibits cell replication & neural function