Anti-Cancer Drugs

Cytosine arabinoside (ara-C, cytarabine) - MOA

Nucleotide analog (modified deoxyribose)

Prodrug

Inhibits DNA polymerase and DNA synthesis

Cytosine arabinoside (ara-C, cytarabine) - Indications

Curative activity AML, especially in high dose therapy

Cytosine arabinoside (ara-C, cytarabine) - Administration

IV

SC

Cytosine arabinoside (ara-C, cytarabine) - Toxicities

• Myelosuppression

• Nausea

• Stomatitis

• Alopecia

Cytosine arabinoside (ara-C, cytarabine) - Resistance

Due to deletion, mutation of dCK or increased deaminase enzymes

Methotrexate - MOA

Inhibits dihydrofolate reductase (DHFR)

Blocks DNA synthesis by blocking thymidine synthesis

Methotrexate - Indications

• Solid epithelial (breast, bladder, head & neck cancers)

• Osteosarcomas

• Hematologic tumors

• Non-cancer indications

  • Rheumatoid arthritis

  • Psoriasis

Methotrexate - Administration

IV

PO

IM

IT

Methotrexate - Toxicities

• Myelosuppression

• Mucositis

• Nephrotoxicity - high dose

  • Prevent by alkalization of urine and hydration

• Toxicity in patients with impaired renal function

  • Glucarpidase (Voraxaze) - prevention therapy

Methotrexate - Resistance

DHFR (gene amplification)

5-Fluorouracil & 5-FUdR - MOA

Uracil analog

Prodrug

Inhibits thymidylate synthetase and blocks DNA synthesis by blocking thymidine synthesis. Some RNA effects.

5-Fluorouracil & 5-FUdR - Indications

Solid tumors (breast, skin, and advanced colorectal cancers)

5-Fluorouracil & 5-FUdR - Administration

PO

IV

Hepatic intra-arterial

Topical

5-Fluorouracil & 5-FUdR - Toxicities

• Myelosuppression

• Stomatitis

• Mucositis

• Diarrhea

5-Fluorouracil & 5-FUdR - Resistance

Possibly thymidylate synthetase overexpression

6-Mercaptopurine & 6-Thioguanine - MOA

Purine nucleoside analogs

Prodrugs

Acts by inhibiting a variety of enzymes involved in purine metabolism and therefore inhibits DNA synthesis and replication

6-Mercaptopurine & 6-Thioguanine - Indications

Largely limited to childhood acute lymphocytic leukemia (ALL)

6-Mercaptopurine & 6-Thioguanine - Administration

PO

6-Mercaptopurine & 6-Thioguanine - Toxicities

Common toxicities

• Bone marrow suppression

• Liver toxicity (jaundice)

Pharmacogenetic screening for TPMT is useful for predicting patients at risk for severe bone marrow toxicity

Less common toxicities

• Nausea / Vomiting

• Death

  • can be lethal if given with allopurinol during chemotherapy-induced tumor cell lysis syndrome

6-Mercaptopurine & 6-Thioguanine - Resistance

Loss of HGRPT activity

2-chlorodeoxyadenosine - MOA

Not metabolized by ADA leading to toxic levels of adenosine

2-chlorodeoxyadenosine - Indications

• Lymphoma

• Hairy cell leukemia

2-deoxycoforomycin - MOA

ADA inhibitor leading to toxic levels of adenosine

2-deoxycoforomycin - Indications

• T-cell lymphoma

• Hairy cell leukemia

Gemcitabine (Difluorodeoxycytidine) - MOA

A nucleotide analog

Prodrug

• Requires intracellular phosphorylation to difluorodCTP (dFdCTP). The dFdCTP competes with dCTP for incorporation into DNA. When dFdCTP is incorporated it inhibits DNA synthesis. Also lowers dNTP pools likely through the inhibition of ribonucleotide reductase

Gemcitabine (Difluorodeoxycytidine) - Indications

• Pancreatic cancer (front line setting for advanced pancreatic cancer, as well as in the adjuvant setting, following surgical resection of the pancreas)

Gemcitabine (Difluorodeoxycytidine) - Administration

IV

Gemcitabine (Difluorodeoxycytidine) - Toxicities

• Myelosuppression (relatively mild)

  • Thrombocytopenia, neutropenia, anemia

• Nausea & vomiting

• Diarrhea & constipation

• Fever

Mechlorethamine (Nitrogen Mustard) - Indications

• Lymphomas

• Bladder cancer

Mechlorethamine (Nitrogen Mustard) - Administration

IV only; strong vesicant if extravasated

Mechlorethamine (Nitrogen Mustard) - Toxicities

• Dose-limiting toxicity

  • Myelosuppression

    • Leukopenia, thrombocytopenia

• Acute

  • Nausea & vomiting

Cyclophosphamide (Cytoxan) - MOA

Prodrug

• Requires metabolic activation by P450 oxidase system

Cyclophosphamide (Cytoxan) - Indications

A variety of solid and hematologic tumors

Cyclophosphamide (Cytoxan) - Administration

IV

PO

Cyclophosphamide (Cytoxan) - Toxicities

• Myelosuppression

• Hemorrhagic cystitis (important)

  • Can be avoided with hydration and high urine flow + thiol administration (e.g mesna)

• Acrolein = suspected bladder toxin

Nitrosoureas - MOA

Metabolized to isocyanates and carbonium ions

Highly lipophilic

Crosses the blood brain barrier & enters CNS

Nitrosoureas - Indications

• Primarily brain tumors

• Lymphomas

• Myeloma

Nitrosoureas - Administration

BCNU - IV

CCNU - PO

Nitrosoureas - Toxicities

• Delayed and profound myelosuppression

• Pulmonary fibrosis

Nitrosoureas - Resistance

Due to increased levels of DNA repair protein, Methyl Guanine Methyltransferase (MGMT)

Platinum Compounds (Cisplatin, Carboplatin) - MOA

Induce multiple types of DNA lesions - bifunctional lesions are those most closely associated with tumor cell kill (DNA inter-strand and intra-strand crosslinks)

Platinum Compounds (Cisplatin, Carboplatin) - Indications

• Drug refractory solid tumors

  • Testicular cancer

  • Ovarian cancer

• Useful in many other solid tumors

Platinum Compounds (Cisplatin, Carboplatin) - Administration

IV

Platinum Compounds (Cisplatin, Carboplatin) - Toxicities

• Nephrotoxicity

  • More severe with cisplatin (can be reduced by hydration and diuretics)

• Ototoxicity

  • Irreversible

• Neurotoxicity

• Nausea & Vomiting

  • Acute and Severe

• Myelosuppression

  • Relatively minor

  • Only 20 - 30% patients with Cisplatin

  • Carboplatin more myelosuppressive

Platinum Compounds (Cisplatin, Carboplatin) - Resistance

Poorly defined

Dacarbazine (DTIC) - MOA

Prodrug

DNA damage, through O6 and N7 positions of Guanine

Dacarbazine (DTIC) - Indications

• Metastatic melanoma

• Hodgkin’s Lymphoma (part of a curative regimen)

Dacarbazine (DTIC) - Administration

IV (tissue destruction if extravasated)

Dacarbazine (DTIC) - Toxicities

• Nausea & vomiting

• Myelosuppression

• Flu-like symptoms

• Stomatitis

Procarbazine - MOA

Prodrug

DNA damage, through O6 and N7 positions of Guanine. Also, DNA strand breaks via H2O2

Procarbazine - Indications

• Hodgkin’s lymphoma

• Glioma

Procarbazine - Administration

PO

Procarbazine - Toxicities

• Bone marrow suppression

• Nausea & vomiting

• Malaise

• Flu-like symptoms

• Stomatitis

• Leukemogenic

Temozolomide - MOA

Prodrug

DNA damage, likely through O6 position of Guanine, and therefore should be considered an alkylating agent

Temozolomide - Indications

• Gliomas (GBM, astrocytoma)

• Melanoma

Temozolomide - Administration

• PO (crosses the blood brain barrier)

Temozolomide - Toxicities

• Nausea & vomiting

• Bone marrow depression (less frequent, can be dose-limiting)

• Elevated liver enzymes

Doxorubicin (Adriamycin) and Daunorubicin - MOA

At least 3 mechanisms participate in cytotoxicity

• Intercalation into DNA with subsequent inhibition of topoisomerase II

• Generation of free radicals from semiquinone intermediates

• Membrane-mediated effects

Doxorubicin (Adriamycin) and Daunorubicin - Indications

Doxo - solid tumors

• Good spectrum

Dauno - largely limited to AML and a few other liquid tumors

• Very little activity against solid tumors

Doxorubicin (Adriamycin) and Daunorubicin - Administration

IV (slow push for both)

Doxorubicin (Adriamycin) and Daunorubicin - Toxicities

Acute dose limiting activity

• Bone marrow depression

Other toxicities

• Stomatitis

• Diarrhea

• Nausea & vomiting

• Alopecia (100%)

• Severe tissue necrosis if extravasated

• Radiation recall effect on skin, soft tissues

• Irreversible cardiotoxicity

  • Lifetime dose-limiting toxicity

    • Total maximum lifetime dose 450-550 mg/mg2 to minimize risk

Doxorubicin (Adriamycin) and Daunorubicin - Resistance

• P-glycoprotein and other related transporters

• Increased free radical scavengers

• Alterations in topoisomerase II levels/activity

Etoposide (VP-16) and Teniposide (VM-26) - MOA

Binds to topoisomerase II and inhibits its DNA unknotting activity

Etoposide (VP-16) and Teniposide (VM-26) - Indications

Eto

• Small cell lung cancer

• Testicular cancer

Teni

• Acute lymphocytic leukemia

• Neuroblastoma

Etoposide (VP-16) and Teniposide (VM-26) - Administration

IV infusion over 30 minutes

Etoposide (VP-16) and Teniposide (VM-26) - Toxicities

• Bone marrow depression (nadir 12 - 16 days)

• Nausea & vomiting

• Some alopecia

Etoposide (VP-16) and Teniposide (VM-26) - Resistance

• Commonly mediated by P-glycoprotein, other transporters, alterations in topoisomerase II activity or function

Bleomycin - MOA

Binds DNA and Fe+2. This causes the generation of reactive oxygen species, resulting in strand scission of the DNA (single- and double-strand breaks)

Bleomycin - Indications

• Testicular cancer

• Head, neck, skin cancer

• Lymphomas

Bleomycin - Administration

IV (slow push)

Bleomycin - Toxicities

Dose limiting toxicity

• Pulmonary → pulmonary fibrosis

• Little myelosuppression

Other toxicities

• Skin hyperkeratoses / hyperpigmentation

• Stomatitis

• Alopecia

• High incidence of fever

Vinblastine and Vincristine - MOA

Bind to tubulins and inhibits their polymerization blocking microtubule assembly, which are necessary for mitotic spindle formation and cell division

Vinblastine and Vincristine - Indications

• Hematologic tumors (esp. lymphoma)

• Solid tumors

  • Testicular, breast, and lung cancer

Vinblastine and Vincristine - Administration

IV (slow push)

Vinblastine and Vincristine - Toxicities

Vinb

• Bone marrow suppression

• Alopecia

Vinc

• Peripheral neurotoxicity

• Little bone marrow suppression

Vinblastine and Vincristine - Resistance

May be mediated by P-glycoprotein and other transporters

Paclitaxel (Taxol) - MOA

Binds to polymerized tubulin and promotes microtubule formation and stabilization, and blocks microtubule disassembly, and inhibiting mitosis and therefore cancer growth

Paclitaxel (Taxol) - Indications

Solid tumors

• Ovarian, breast, non-small cell lung cancers

Paclitaxel (Taxol) - Administration

IV injection

Paclitaxel (Taxol) - Toxicities

Dose-limiting

• Peripheral neuropathy

• Granulocytopenia

Mild-moderate

• Nausea & vomiting

Paclitaxel (Taxol) - Resistance

Commonly mediated by P-glycoprotein and other transporters

L-Asparaginase - MOA

Without sufficient amounts of asparagine, protein synthesis is blocked and subsequently proliferation is halted in asparagine synthetase-deficient tumor cells

L-Asparaginase - Indications

• Acute lymphocytic leukemia (Pediatric & Adult)

• Lymphoma

• Mast cell tumors

L-Asparaginase - Administration

IV

IM

L-Asparaginase - Toxicities

• Nausea

• Fever

• Allergic reaction

• CNS depression

• Pancreatitis

• NO BONE MARROW DEPRESSION

5-aza-2’ deoxycytidine & 5-azacytidine - MOA

Pyrimidine analogs

Prodrug

Bioactivated to its triphosphate form, it incorporates into DNA, and inhibits DNA methyltransferase, resulting in genomic demethylation

5-aza-2’ deoxycytidine & 5-azacytidine - Indications

Myelodysplastic Syndrome (Pre-leukemia)

5-aza-2’ deoxycytidine & 5-azacytidine - Administration

IV

SC

Note:

• Drug is unstable (4 hours in lactated Ringer’s solution)

5-aza-2’ deoxycytidine & 5-azacytidine - Toxicities

• Bone marrow suppression

• Nausea & vomiting

All Trans Retinoic Acid (ATRA) and related retinoids - MOA

Binds to retinoid receptors and induces changes in gene expression driving terminal differentiation of tumor cells

All Trans Retinoic Acid (ATRA) and related retinoids - Indications

Acute Promyelocytic Leukemia, specific form (M3) of AML, in which the pathogenetic lesion is the PML-RARa translocation (t15;17)

All Trans Retinoic Acid (ATRA) and related retinoids - Administration

Oral

• Most often combined in regimen of araC + daunorubicin

• Sometimes combined with Arsenic trioxide

All Trans Retinoic Acid (ATRA) and related retinoids - Toxicities

• Skin (photosensitivity)

• Headaches

• Cardiovascular (decrease heart function)

• “Retinoic acid syndrome'“

  • Fever, fluid weight gain, respiratory distress, pulmonary infiltrates, pleural & pericardial effusions

Histone Deacetylase Inhibitors (HDACi) - MOA

Inhibit histone deacetylase complexes of cancer-silenced genes and reprogramming their gene expression to a more benign or drug sensitive state

Vorinostat (SAHA) - Indication

• Histone Deacetylase Inhibitors (HDACi)

Cutaneous T-cell lymphoma

Glucocorticoids (Dexamethasone, Prednisone, Hydrocortisone) - MOA

Hormone Agonist

• Glucocorticoid binds to its specific receptor, translocates to the cell nucleus, alters gene expression, and causes programmed cell death of the cancer cell (apoptosis)

Glucocorticoids (Dexamethasone, Prednisone, Hydrocortisone) - Indications

• Lymphomas

• Multiple myeloma

• Acute and chronic lymphocytic leukemia

• Brain tumors or metastases

  • Shrinks edema around tumor

• In high doses blocks cortical pathways of emesis

  • Learned response

• Hypercalcemia associated with malignancy

Glucocorticoids (Dexamethasone, Prednisone, Hydrocortisone) - Administration

IV

IM

PO

Glucocorticoids (Dexamethasone, Prednisone, Hydrocortisone) - Toxicities

• Adrenal suppression

• Edema

• Electrolyte changes

• Ulcer

• Immunosuppression

• Muscle weakness

• Dermatologic

• Can exacerbate diabetes

• Excitation in high doses

Progestins (Megestrol (Megace) , Medroxyprogestone (Depo-Proveras)) - MOA

Hormone agonist

Synthetic progesterone

Bind to progestin receptors (PR) which:

• Decreases number of ER

• Enhances metabolism of estrogen