16. Anti-cancer Drugs

List the classifications of anti-cancer drugs and give examples of each.

1. Anti-metabolites: methotrexate

2. Alkylating agents: cyclophosphamide

3. Antibiotics: doxorubicin

4. Mitotic spindle poisons: vinca alkaloids; vincristine, vinblastine

5. Hormones: prednisone, tamoxifen, anastrozole

6. Monoclonal antibodies: trastuzumab

Anti-metabolites - Methotrexate

Describe anti-metabolites and their mechanism of action.

• Structurally related to normal compounds that exist in cell

• Interfere w/availability of normal purine or pyrimidine nucleotide precursors, either by inhibiting synthesis or by competing with them in DNA or RNA synthesis

Anti-metabolites - Methotrexate

Anti-metabolites are ____ _____ ________, and their maximal cytotoxic effects are in the ___ phase.

• cell cycle specific

• S-phase

Anti-metabolites - Methotrexate

List characteristics of methotrexate.

• Folic acid analogue

• Oldest

• Highly efficacious anti-neoplastic drugs

Anti-metabolites - Methotrexate

Describe the mechanism of methotrexate.

• Structurally related to folic acid

• Acts as antagonists by inhibiting mammalian dihydrofolate reductase (DHFR); enzyme that converts folic acid to its active, coenzyme form, tetrahydrofolic acid

• Also inhibits thymidylate synthase + other enzymes involved in folate metabolism and DNA synthesis

Anti-metabolites - Methotrexate

List the therapeutic uses of methotrexate.

Usually in combination with other drugs

1. Effective against acute lymphocytic leukemia, breast cancer, bladder cancer, and head and neck carcinomas

2. Low-dose MTX is effective as single agent against certain inflammatory diseases e.g. severe psoriasis, rheumatoid arthritis, and Crohn’s disease

Anti-metabolites - Methotrexate

List the adverse effects of methotrexate.

• Nausea

• Vomiting

• Bone marrow depression

Alkylating Agents - Cyclophosphamide

Alkylation of ___ is probably the most crucial cytotoxic reaction that is _______ to the tumor cells. They exert their cytotoxic effects by __________ binding to ___________ groups on various cell constituents. Alkylating agents do not discriminate between _______ and _______ cells, even though they are most toxic for _______ ________ cells.

• DNA

• lethal

• covalently

• nucleophilic

• cycling

• resting

• rapidly dividing

Alkylating Agents - Cyclophosphamide

Why is cyclophosphamide one of the most popular alkylating agents used in many solid tumors?

Prominent immunosuppressant property

Alkylating Agents - Cyclophosphamide

List the adverse effects of cyclophosphamide.

Alopecia and cystitis (due to another metabolite, acrolein)

Antibiotics - Doxorubicin

Antibiotics owe their cytotoxic action primarily to their _____________ with ___, which cause ___________ of DNA function. They are cell cycle ____________.

• interactions

• DNA

• disruption

• non-specific

Antibiotics - Doxorubicin

Describe the mechanism of doxorubicin.

Doxorubicin-derived free radicals can induce membrane lipid peroxidation, DNA strand scission, and direct oxidation of purine or pyrimidine bases, thiols, and amines

Antibiotics - Doxorubicin

What is the most serious adverse reaction of doxorubicin?

Irreversible, dose-dependent cardiotoxicity

Microtubule Inhibitors/Mitotic Spindle Poisons

Vincristine and vinblastine are _____ _________. They bind to microtubular protein ‘_______’, prevent its _____________ and ________ of microtubules, cause disruption of mitotic _______, and interfere with ____________ function. They are cell cycle ________ and act in the ________ phase.

• mitotic inhibitors

• tubulin

• polymerization

• assembly

• spindle

• cytoskeletal

• specific

• mitotic

Microtubule Inhibitors/Mitotic Spindle Poisons

Vincristine and vinblastine are _______-acting drugs, useful in inducing __________ in childhood acute _____________ _______.

• rapidly

• remission

• lymphoblastic leukemia

Microtubule Inhibitors/Mitotic Spindle Poisons

List the adverse effects of microtubule inhibitors.

Peripheral neuropathy and alopecia

Steroid Hormones and their Antagonists

Describe prednisone and what it is used for.

• Potent

• Synthetic

• Anti-inflammatory corticosteroid

• Primarily employed to induce remission in patients with acute lymphocytic leukemia & in treatment of both Hodgkin and non-Hodgkin lymphomas

Steroid Hormones and their Antagonists

Describe tamoxifen and what it is used for.

• Estrogen antagonists with some estrogenic activity

• Classified as selective estrogen receptor modulator (SERM)

• Used for first-line therapy in treatment of estrogen receptor positive (ER+ve) breast cancer

• Used prophylactically in reducing breast cancer occurrence in high-risk women

Steroid Hormones and their Antagonists
Anastrozole is an _________ inhibitor. The aromatase reaction is responsible for extra-adrenal synthesis of _________, which takes place in _____, fat, muscle, skin, and breast tissues, including breast _____________. __________ aromatization is an important _____ of estrogen in _______________ women. Aromatase inhibitors ________ the production of estrogen in these women. They are ______ active and cause almost a total suppression of estrogen synthesis.

• aromatase

• estrogen

• liver

• malignancies

• Peripheral

• source

• postmenopausal

• decrease

• orally

Define and describe targeted therapy.

• Drugs targeted at pathways, processes, and proteins which are uniquely disrupted in cancer cells or in tumor microenvironment

• E.g. receptors, genes, angiogenesis, tumor pH

List the advantages of targeted therapy.

• More effective treatments that can attack specific breast cancer cells without harming normal cells

• Commonly used in combination with traditional chemotherapy with fewer severe adverse effects

Monoclonal Antibodies - Trastuzumab

Describe trastuzumab and its functions.

• Humanized monoclonal antibody, specifically targets extracellular domain of HER2 growth receptor

• In patients w/metastatic breast cancer, overexpression of transmembrane human epidermal growth factor receptor protein 2 (HER2) is seen in 25-30% of patients

Monoclonal Antibodies - Trastuzumab

Describe the mechanism of trastuzumab.

• Binds to HER2 sites in breast cancer, gastric cancer, etc, and inhibits proliferation of cells that overexpress the HER2 protein → decreasing no. of cells in S-phase

• By binding to HER2, it blocks downstream signaling pathways, induces antibody-dependent cytotoxicity, and prevents release