[1.1] Anti-cancer drugs

Cancer

• neoplastic disease

• term used for diseases in which abnormal cells divide without control and can invade other tissues due to mutations in the DNA of cells

Cyst

abnormal sac or closed cavity filled with liquid or semisolid matter; movable

Tumor

mass that is observed as a lump in a body; neoplasm; non-movable

Inflammatory breast CA

• no lump; but is still cancer

• makes the skin on the breast look red and feel warm

• the affected breast may become larger or firmer, tender, or itch

Signs and Sx of Inflammatory Breast CA

• sudden visible enlargement

• discoloration

• tenderness and pain

• inward turning of nipple

Abilities of cancer cells

• melts the collagen and connective tissues

• capable of intravastion

• capable of extravasation

• capable of angiogenesis

Angiogenesis

process involving the growth of new blood vessels from pre-existing vessels

Cancer tx

• Surgery

• Radiation therapy

• Chemotherapy

• Hormone therapy

• Stem cell transplant

Chemotherapy

treatment of cancer by using cytotoxic and other drugs

Goals of chemotherapy

• palliation

• cure

• adjuvant

• neoadjuvant

Palliation

• alleviation of symptoms; prolong life

Adjuvant

• surgery and/or radiotherapy then chemotherapy; done after initial tx

Neoadjuvant

• chemotherapy then surgery and/or radiotherapy

Most common side effects of chemotherapy

affects all rapidly proliferating cells

• hair loss

• loss of appetite

• N/V

• diarrhea

• bone marrow suppression

• fatigue

Sx manifest cell death*

Chemotherapuetic agents

1. Cell-cycle

   • phase-sppecific

   • phase-nonspecific

2. Cell-cycle non-specific

Phases of Cell Cycle

Phase-specific agents

most active against cells that are in a specific phase of the cell cycle

Drugs used for M-phase

Vinca alkaloids

Drugs used for G1-phase

• Asparaginase

• Prednisone

Drugs used for S-phase

Antimetabolites

Drugs used for G2-phase

• Bleomycin

• Etoposide

Phase-Non specific agents

effective while cells are in the active cycle but do not require that the cell be in a particular phase

Drugs used for Phase-Non specific

• Alkylating agents

• Antitumor antibiotics

• Cisplatin

Cell-cycle Non-specific agents

effective in all phases including G0

Drugs used for Cell-cycle Non-specific

• Nitrosoureas

• Radiation

Plant alkaloids

• Vinca alkaloids - microtubule damaging agents

• Taxanes - microtubule damaging agents

• Camptothecins - topoisomerase inhibitors

• Podophyllotoxins - topoisomerase inhibitors

Vinca alkaloids

starts with “vin-”

• Vincristine

• Vinblastine

• Vindesine

• Vinorelbine

Vinca alkaloids MOA

promote depolymerization (disassembly) and prevent the rescue of microtubules

*detailed explanation:

• blue tubulin (GDP-bound tubulin) is more unstable than green tubulin (GTP-bound tubulin)

• prevent the rescue of destroyed microtubules → inhibiting mitotic spindle formation, chromosomal migration, and cell division

Vinblastine

used to treat testicular cancer which can cause alopecia, bone marrow suppression, N/V

Vincristine

used to treat Hodgkin’s lymphoma and Wilm’s tumor which can cause neurotoxicity or peripheral neuropathy

Taxanes

ends with “-taxel”

• Docetaxel

• Paclitaxel

• Cabazitaxel

Taxanes MOA

• bind to and stabilize microtubules by enhancing tubulin polymerization

• forming weak polymers, clogged microtubules

Podophyllotoxins

ends with “-side”

• Etoposide - G2

• Teniposide - late S, early G2

Podophyllotoxins MOA

inhibits topoisomerase II causing double strand DNA breaks

Campothecins

ends with “-tecan”

• Topotecan

• Irinotecan

Campothecins MOA

inhibits topoisomerase I causing single strand DNA breaks

Irinotecan

pro-drug metabolized to an active topoisomerase I inhibitor, SN-38

Irinotecan

used to treat colon rectal cancer

Antibiotic Anticancer Agents

• Anthracyclines

• Bleomycin

• Dactinomycin

• Plicamycin

• Mitomycin

Anthracyclines

ends with “-rubicin”

• Daunorubicin

• Doxorubicin

• Idarubicin

• Epirubicin

Anthracyclines MOA

intercalation → stabilize / inhibit topoisomerase II after it has cut and unwinded the DNA strand for replication → prevents topoisomerase from reattaching the broken ends of DNA

Intercalation

process by which drug slides between DNA base pairs causing additional DNA strand breaks

Anthracyclines

causes cardiotoxicity, total alopecia, bone marrow suppression, red or orange discoloration of the urine

Doxorubicin

used to treat BOLT cancer (breast, ovarian, lung, thyroid)

Daunorubicin, Idarubicin, Doxorubicin

used to treat acute leukemia

Dactinomycin MOA

intercalation between C-G base pairs → block RNA polymerase → inhibit DNA and RNA synthesis

RNA polymerase

an enzyme that is responsible for copying a DNA sequence into an RNA sequence

Dactinomycin

potent vesicant, used in pediatric cancers such as Wilm’s tumor (kidney CA) but may cause radiation recall

Radiation recall

• the skin from prior radiation therapy can become red and appear damaged again

• hyperpigmentation and thickening of the skin

Plicamycin

• formerly Mithramycin used to treat testicular CA

Plicamycin

binds to DNA in the presence of Mg2+ or other divalent cations, where it interrupts RNA synthesis

Plicamycin

may cause bone marrow suppression, liver toxicity, hypocalcemia

Mitomycin

• second line agent for metostatic colon cancer

Cervical cancer treatment combination

• Bleomycin

• Vincristine

• Mitomycin

Stomach, pancreas, lung cancer treatment combination

• Mitomycin

• Doxorubicin

• 5-fluorouracil

Mitomycin MOA

metabolized intracellularly → binds to guanine residues → cross linking of DNA strands (alkylation)

Bleomycin

outstanding side effect is lung toxicity

Bleomycin MOA

oxidation of DNA-bleomycin-Fe(II) complex → production of toxic free radicals → inhibit DNA synthesis

Hormonal Agents

• SERM agents

SERM

• selective estrogen receptor modulators

• drug that have estrogen receptor agonist or antagonist properties depending on the target tissue

SERM drugs that have antiestrogen activity

• Tamoxifen

• Toremifene

• Raloxifene

*used to treat breast CA

Tamoxifen, Toremifene, Fulvestrant

used to treat Hormone receptor-positive breast CA

Tamoxifen, Raloxifene

used for risk reduction for women at high risk of breast CA

Raloxifene

used to treat osteoporosis due to its estrogenic activity in bone

*since estrogen is used to increase bone density

Toremifene

may cause QT prolongation

Tamoxifen

may increase the risk for endometrial CA (estrogenic activity in endometrium)

SERM drugs

carry the risk for thromboembolic events

Fulvestrant MOA

• estrogen receptor antagonist

• detailed:

  • competitively binds to the estrogen receptor on tumors; blocking the action of estrogen to inhibit tumor growth

• increases liver enzymes

SERM drugs, Fulvestrant

may cause hot flashes

Aromatase inhibitors

ends with '‘-zole’

• Aminoglutethimide

• Anastrazole

• Letrozole

Aromatase inhibitors

used to treat breast CA in postmenopausal women

Aromatase inhibitors MOA

• inhibits conversion of cholesterol to pregnenolone

• inhibits extra adrenal synthesis of estrone and estradiol

• inhibits aromatase enzyme and prevent the conversion of androstenedione to estrone, testosterone to estradiol (aromatization)

• overall: inhibit estrogen formation

Anastrazole and Letrozole

may cause hypercholesterolemia

Aromatase inhibitors drugs

• Not benefit postmenopausal women

• Increase risk for ischemic CV events

GnRH agonists

• Leuprolide

• Goserelin

GnRH agonists MOA

initially stimulating FSH and LH → negative feedback → reduced testicular synthesis

long term → suppression of LH and FSH → decrease in levels of testosterone, dihydroxytestosterone, estrogen

Leuprolide, Degarelix

used to treat advanced prostate CA

*MOA is different

*Leuprolide causes tumor flare

Goserelin

used to treat advanced prostate CA, advanced breast CA

Degarelix MOA

• GnRH antagonist

• acts more quickly than GnRH agonists

• may cause wt gain

Degarelix

precaution for ADT (Androgen Deprivation Therapy) since it may increase risk for CV disease

Androgen Synthesis Inhibitors

• Abiraterone

• Ketoconazole

Androgen Synthesis Inhibitors MOA

inhibits CYP17 → inhibit formation of testosterone precursor

CYP17

enzyme required for androgen biosynthesis

aka 17a-hydroxylase and 17,20-lyase

Abiraterone, Ketoconazole, Enzalutamide

used to treat metastatic castration-resistant prostate CA

Abiraterone

causes edema and fatigue

Ketoconazole

causes N&V, skin rash

First generation antiandrogens

ends with “-lutamide”

• Flutamide

• Bicalutamide

• Nilutamide

First generation antiandrogens MOA

inhibit binding of androgens to the androgen receptor → block testosterone effects at the androgen receptor → prevent testosterone stimulation of cell growth in prostate CA

Antiandrogens

used for advanced prostate CA in combination with GnRH agonist or surgical castration

Flutamide

may cause hepatic failure

Nilutamide

may cause interstitial pneumonitis

Second generation antiandrogens MOA

pure androgen receptor signaling inhibitor which leads to cellular apoptosis and decreased prostate tumor volume

Mechlorethamine

nitrogen based analog of mustard gas - cytotoxic and vesicant agent

Alkylating agents MOA

• The alkylating agents involve intramolecular cyclization to form an ethyleneimonium ion and/or carbonium ion (electrophilic center)

• They react with a base such as N7 of guanine in DNA producing an alkylated purine

• Alkylation of a second guanine residue results in cross linking of DNA strands

• Alkylation of guanine can result in miscoding through abnormal base pairing with thymine or results to DNA strand breakage

Alkylating agents

• Nitrogen mustards

• Nitrosoureas

• Alkylsulfonate

• Platinum analogs

Mechlorethamine

used to treat Hodgkins lymphoma

Carmustine, lomustine

used to treat Brain tumors, melanoma & lymphoma

Cyclophosphamide

used to treat Breast, testicular, ovarian cancer, non- Hodgkin lymphoma

Ifosfamide

used to treat testicular, sarcoma, non-Hodgkin lymphoma

Cisplatin, Carboplatin

used to treat Lung, ovarian, bladder and testicular cancer, and colorectal (Oxaliplatin)