Antineoplastic Drugs

Benign Cancer

Localized, well-differentiated, non-invasive

Malignant Cancer

Poorly differentiated, invades tissues, metastasizes, competes for nutrients

Etiology of Cancer

Smoking, obesity, alcohol, UV radiation, HPV, Hep B/C, genetics

Most antineoplastic drugs have?

Systemic effects (regardless of tumor type)

Cell Cycle Phases

G0 → G1 → S → G2 → M

Growth Fraction

Ratio of proliferating to resting cells. High in leukemias/lymphomas, low in solid tumors

Cancer Treatment Strategies

Surgery → Solid Tumors / Radiation → Localized Therapy / Chemotherapy → Metastatic Cancers

Obstacles to Chemotherapy

Toxicity to normal cells, drug resistance, tumor heterogeneity, limited drug access, early detection challenges, cure requires 100% cell kill

Strategies to Maximize Chemotherapy Benefits

Intermittent dosing, combination therapy, schedule optimization, regional delivery, supportive care

Cytotoxic Drugs

Drugs that kill/inhibit the growth of rapidly dividing cells, both malignant and normal, often non-selective for cancer cells which damage normal rapidly dividing cells

3 Major Classes of Anticancer Drugs

Cytotoxic Drugs + Hormonal Agents + Targeted Therapies

Alkylating Agents MOA

Alkylate (cross-link) DNA, preventing DNA replication and cell division, l/t cancer cell death

Absorption of Alkylating Agents

Many are well absorbed orally, others require IV

Distribution of Alkylating Agents

Wide, some cross the blood-brain barrier

Metabolism of Alkylating Agents

Some are prodrugs activated in the liver

Excretion of Alkylating Agents

Renal, dose adjustment needed in renal impairment

Adverse Reactions of Alkylating Agents

Bone marrow suppression, N/V, alopecia, mucositis

Contraindications of Alkylating Agents

Severe bone marrow suppression, active severe infection, pregnancy, renal/hepatic impairment 

Nursing Implications of Alkylating Agents

Monitor CBC, encourage hydration, administer mesna for uroprotection

Platinum Compounds Examples

“-Platin”

Platinum Compounds MOA

DNA cross-linking, form intra- and inter-strand DNA cross-links

Clinical Uses of Platinum Compounds

Treatment of solid tumors

Pharmacokinetics of Platinum Compounds

IV administration, wide distribution, poor CNS penetration, not metabolized by liver

Adverse Reactions of Platinum Compounds

Nephrotoxicity, ototoxicity, peripheral neuropathy, bone marrow suppression

Contraindications of Platinum Compounds

Pre-existing severe renal impairment, hearing loss, pregnancy, neuropathy

Clinical Uses of Antimetabolites

Leukemias, lymphomas, breast, GI, head + neck, ovarian cancers

Antimetabolites MOA

Mimic normal cell metabolites, inhibit enzymes involved in DNA/RNA synthesis

When are antimetabolites most effective during?

DNA Synthesis (S-Phase)

Methotrexate MOA

Inhibits dihydrofolate reductase (DHFR), blocking tetrahydrofolate formation (FH4), prevents synthesis of thymidylate + purine nucleotides

Clinical Uses of Methotrexate

Acute lymphoblastic leukemia, lymphomas, breast, head and neck, osteosarcoma, choriocarcinoma

Methotrexate Contraindications

Pregnancy, severe hepatic/renal impairment, existing bone marrow suppression

Methotrexate Adverse Reactions

Myelosuppression, mucositis, hepatoxicity, nephrotoxicity, pulmonary toxicity

Pyrimidine Analogs MOA

Mimic natural pyrimidines (cytosine, thymine, uracil)

5-FU (Pyrimidine Analog)

Inhibits thymidylate synthase, blocking thymidine synthesis

Clinical Uses of Capecitabine

Colorectal, breast, GI, head and neck cancers, topical for actinic keratosis

Cytarabine

Inhibits DNA polymerase, impairs DNA synthesis

Cytarabine Clinical Uses

Acute myeloid and lymphoblastic leukemias, CNS leukemia/lymphoma

Adverse Reactions of Pyrimidine Analogs

Myelosuppression, GI toxicity, hand foot syndrome, neurotoxicity

Contraindications of Pyrimidine Analogs

Severe bone marrow suppression, pregnancy, severe hepatic/renal impairment

Purine Analogs MOA

Mimic natural purines (adenine, guanine)

6-Mercaptopurine

Inhibit enzymes involved in purine synthesis and metabolism l/t faulty DNA/RNA synthesis

Clinical Uses of 6-Mercaptopurine

Acute lymphoblastic leukemia

Adverse Effects of 6-Mercaptopurine

Myelosuppression, hepatoxicity, GI toxicity, immunosuppression 

Contraindications of Purine Analogs

Severe bone marrow suppression, pregnancy, hepatic impairment

Anthracyclines

“-Rubicin”

Non-Anthracyclines

”-Mycin”

Clinical Uses of Antitumor Antibiotics

Leukemias, lymphomas, breast/ovarian/lung sarcomas

Antitumor Antibiotics MOA

DNA Intercalation (insert between DNA base pairs and inhibits topoisomerase II, disrupting DNA/RNA synthesis)

Adverse Reactions of Antitumor Antibiotics

Myelosuppression, cardiotoxicity, extravasation injury, alopecia, red urine

Contraindications of Antitumor Antibiotics

Pre-existing cardiac disease, severe hepatic impairment, prior anthracycline exposure

Clinical Uses of Mitotic Inhibitors

Leukemias, lymphomas, breast/lung/testicular cancers

Vinca Alkaloids MOA

Bind to tubulin, inhibit microtubule assembly, block mitosis at metaphase (m-phase specific)

Taxanes MOA

Stabilize microtubules, prevent disassembly, block mitosis

Adverse Reactions of Vincristine

Peripheral neuropathy, constipation, SIADH, minimal myelosuppression

Adverse Reactions of Vinblastine

Myelosuppression, less neurotoxicity

Adverse Reactions of Taxanes

Myelosuppression, neuropathy, hypersensitivity reactions, alopecia, myalgias

Contraindications of Mitotic Inhibitors

Pre-exisiting neuropathy, severe hepatic impairment, biliary obstruction, elderly

Clinical Uses of Topoisomerase Inhibitors

Leukemias, lymphomas, lung/ovarian/colorectal cancers

Topoisomerase II Inhibitors

“-Poside”

Topoisomerase I Inhibitors

“-Tecan”

Topoisomerase II Inhibitors MOA

Prevent DNA unwinding and replication, cause DNA strand break (S + G2 phase)

Topoisomerase I Inhibitors MOA

Prevent DNA repair, cause single-strand breaks (S phase)

Adverse Reactions of Topoisomerase Inhibitors

Myelosuppression, GI toxicity, alopecia, hypotension, secondary leukemia 

Contraindications of Topoisomerase Inhibitors

Severe bone marrow suppression, hepatic/renal impairment, elderly, prior GI disease

Asparaginase MOA

Enzyme that depletes asparagine, inhibits protein synthesis in leukemic cells

Asparaginase Clinical Use

Acute lymphoblastic leukemia

Adverse Reactions of Asparaginase

Hypersensitivity, pancreatitis, coagulopathy, hepatotoxicity, CNS depression

Contraindications of Asparaginase

Pancreatitis, severe hepatic dysfunction

Hydroxyurea MOA

Inhibits ribonucleotide reductase, affecting DNA synthesis

Clinical Use of Hydroxyurea

Chronic myeloid leukemia, sickle cell

Adverse Reactions of Hydroxyurea

Myelosuppression, GI upset, skin changes

Mitotane MOA

Cytotoxic drug that selectively inhibits mitochondria in adrenal glands

Clinical Uses of Mitotane

Adrenal Carcinoma

Adverse Effects of Mitotane

GI upset, CNS depression, rash

Hormonal Agents

Used primarily for hormone-sensitive cancers (breast, prostate, endometrial), work by blocking/modifying effects of endogenous hormones that promote tumor growth

Tamoxifen MOA

Selective estrogen receptor modulator (SERM), blocks estrogen receptors in breast tissue, partial agonist in other tissues (endometrium, bone)

Fulvestrant MOA

Pure estrogen receptor antagonist, promotes receptor degradation

Tamoxifen Clinical Uses

ER-positive breast cancer (treatment and prevention)

Fulvestrant Clinical Uses

Advanced/metastatic ER-positive breast cancer

Adverse Reactions of Antiestrogens

Hot flashes, night sweats, vaginal discharge, increased risk of endometrial cancer, bone pain, hypercalcemia

Contraindications of Antiestrogens

History of DVT/PE, pregnancy, endometrial cancer

Aromatase Inhibitors MOA

Inhibit aromatase enzyme, blocking conversion of androgens to estrogens in peripheral tissues (reduces estrogen levels in postmenopausal women)

Clinical Uses of Aromatase Inhibitors

First-line or adjuvant therapy for ER-positive breast cancer in postmenopausal women

Aromatase Inhibitors Adverse Reactions

Musculoskeletal pain, arthralgia, osteoporosis, increased fracture risk, hot flashes, night sweats

Contraindications of Aromatase Inhibitors

Premenopausal women (ineffective), pregnancy

GnRH Agonist (Leuprolide) MOA

Initially increase, then suppress LH/FSH l/t decreased testosterone production (“chemical castration”)

GnRH Antagonist (Degarelix) MOA

Directly block GnRH receptors, rapidly suppress testosterone without initial surge

Androgen Deprivation Therapy Clinical Uses

Advanced/Metastatic Prostate Cancer

Adverse Reactions of Androgen Deprivation Therapy

Hot flashes, decreased libido, ED, initial tumor “flare” with agonists, gynecomastia

Contraindications of Androgen Deprivation Therapy

Pregnancy, hypersensitivity 

Androgen Receptor Blockers MOA

Competitively inhibit androgen receptors, blocking testosterone effects on prostate cancer cells

Clinical Uses of Androgen Receptor Blockers

Used with GnRH agonists for advanced prostate cancer

Adverse Reactions of Androgen Receptor Blockers

Hepatotoxicity, decreased libido, hot flashes, gynecomastia

Androgen Receptor Blockers Contraindications

Severe hepatic impairment, pregnancy

Monoclonal Antibodies “-Zumab” MOA

Bind specific antigens on cancer cells, blocking growth signals or marking cells for immune destruction

Adverse Reactions of Monoclonal Antibodies

Infusion reactions, cardiotoxicity, pulmonary toxicity, immunosuppression, risk of infections