-All the drugs associated with cancer are meant to cause apoptosis within the cancer cells. That means they interrupt some metabolic process in the cell that causes it to die.

You can interrupt the metabolic processes anywhere between purine and pyrimidine synthesis to protein synthesis:

1 Drug between purine and pyrimidine synthesis and ribonucleotides

2 Drugs between ribonucleotides and deoxyribonucleotides

1 drug between deoxyribonucleotides and DNA

3 classes of drug between DNA and RNA

Neoadjuvant chemotherapy is prior to surgery, Adjuvant is after surgery, and maintenance chemotherapy is used to maintain remission

Therapy mainly targets rapidly dividing cells, and nondividing cells tend to survive therapy.

We have two main classes of cancer drug: Cell cycle-specific drugs, and Cell cycle non-specific drugs. The non-specific variation is more effective, but are also more toxic.

Cell Cycle Specific

-Antimetabolites

-Bleomycin

-Etoposide

-Vinca alkaloids

Cell Cycle non-specific

-Alkylating agents

-Antibiotics

-Cisplatin

-Nitrosoureas

Log Kill Phenomenon

-Cancer cell death follows 1st-order kinetics. This means the death of the cells can be described logarithmically

-if there is 10^4 cells remaining after treatment that is called a 5-log kill

-what is remaining is considered incredibly potent/dangerous, and further treatment is still required.

Pharmacologic Sanctuary

-There are some parts of the body (like the CNS) where our drugs cannot reach. This provides a “safe space” for cancer cells, and we may need irradiation or intrathecal administration to kill off the rest of the cancer.

-Individual solid tumors can also create their own sanctuaries within themselves.

Treatment Regiments

-Most often we refer to combination of drugs to treat cancer. We use many different classes for the best effect, and you can get a really effective combination of drugs if they have different mechanisms of action.

-If they have overlapping toxicities, they can be combined after reducing both doses.

-Non overlapping toxicities create potent combinations.

Treatment Issues

-Our biggest issue is resistance via natural selection. To avoid this, treatments is intensive, short term, and intermittent. Multidrug resistance involves cross-resistance and p-glycoprotein. Some cancers are just naturally resistant (melanoma).

-Cancer drugs are toxic. They’ll kill ANY cells that rapidly divide, including bone marrow cells and mucous lining cells. Because of this, they all have narrow therapeutic indexes. Expect vomiting and stomach issues, alopecia, myelosuppression (immune system impairment), toxicity to the bladder, heart or lungs.

-Tumor lysis syndrome is when a huge amount of cells die and their metabolic remains circulate in the bloodstream.

-Some cancer drug agents cause DNA changes, that may induce cancer. This is called treatment-induced tumorigenesis. This kind of cancer isn’t responsive to treatment

Antimetabolites (Cell Cycle Specific to the S phase)

-Block formation of nucleotides and/or interfere with DNA/RNA synthesis

-Many of these end in “-bine.” If it does not, it has a number (5 or 6) or it’s methotrexate

1. Methotrexate

   1. Inhibits DHFR antagonistically, which uses folic acid to create nucleotides. Treats ALL cancer.

   2. A lack of (or amplification of) DHFR, thymidylate synthase, or glutamylation enzyme creates resistance.

   3. CAN WORK ON LUNG CANCER.

   4. Cancer has created some methods of resistance against methotrexate. They kick out MTX, reduce DHFR to make MTX useless, or overamplify DHFR to where MTX can’t stop them all.

   5. Poor BBB penetration and erratic oral absorption. Causes GI issues, hepatotoxicity, anorexia and myelosuppression. Metabolites cause crystalluria. Administer folic acid or leucovorin to manage toxicity.

2. 6 Mercaptopurine

   1. 6-MP will converted into TIMP, which inhibits nucleotide synthesis and forces the creation of nonfunctional DNA and RNA.

   2. Increased dephosphorylation, increased metabolism, and reduced HGPRT (which makes TIMP) causes resistance.

   3. Poor BBB penetration and erratic oral absorption. Causes GI issues, hepatotoxicity, anorexia and myelosuppression.

3. 5-Flurouracil

   1. 5-FU depletes cells of thymidine, reducing DNA synthesis and creating nonfunctional RNA. It’s typically used for slow growing tumors.

   2. Severe Gastric Toxicity. Wide distribution, penetrates the BBB and is processed hepatically.

   3. Over/under-expression of DPD causes ineffective doses or toxicity respectively in certain patients.

4. The “-bines.”

   1. All of them (except gemcitabine) treat AML.

   2. Gemcitabine can treat pancreatic cancer and NSCLC

   3. Capecitabine treats METASTATIC BREAST CANCER

Antitumor Antibiotics

-Wreck DNA replication, and makes them fragile to breaking. They also generate an absurb amount of free radicals, damaging a number of DNA creation/copying parts, and destroy various other metabolic parts.

-Largely cell cycle-nonspecific

-All of these end in “-icin and -ycin.”

1. Anthracyclines

   1. The most important is Doxorubicin

   2. They cause DNA fragmentation, synthesis, ruin DNA repair enzymes, and generate free radicals that tear cells apart.

   3. Require IV administration and can cause red discoloration in veins.

   4. Binds to plasma proteins, widely distributed, and poor CNS penetration. Hepatically metabolized

   5. Irreversible cardiotoxicity. Can cause heart failure.

2. Bleomycin

   1. Cell cycle specific at the G2 phase, and used for testicular cancer

   2. Works mainly through the creation of free radicals by binding iron and DNA.

   3. Increased bleomycin enzymes (hydrolase and amidase), efflux, or upregulation of DNA repair mechanisms creates resistance.

   4. Inactivating enzyme distribution means lung and skin toxicity. Renal elimination.

   5. Pulmonary toxicity (fibrosis) along with mucocutaneous reactions.

Alkylating Agents

-Bind covalently to cellular components and in DNA to render them unusable.

-Cell Cycle Nonspecific

-Mutagenic and can cause secondary malignancies

1. Cyclophosphamide and Ifosfamide

   1. Hydrolyzed/Activated by CYP450 to alkylate DNA and disable it.

   2. Resistance builds with upregulated DNA repair, decreased drug permeability, and cross resistance.

   3. Cyclophosphamide is available both Orally and IV; hepatically metabolized.

      1. Ifosfamide is IV only, hepatically metabolized and renally eliminated.

   4. Bladder toxicity and Hemorrhagic cystitis

2. Nitrosoureas (Carmustine and Lomustine)

   1. Can penetrate the CNS to treat brain tumors

      1. Large volume of distribution

   2. Alkylates DNA and replication mechanisms. Also inhibits multiple vital reductases.

   3. Resistance builds with increased DNA repair, decreased drug permeability, and cross resistance.

   4. Carmustine is available via IV

      1. Lomustine is available orally

   5. Toxicity to the liver, nervous system, genitals, and immune system.

3. Dacarbazine

   1. Must undergo biotransformation to it’s active form, MTIC

   2. Attacks nucleophilic groups, and alkylates DNA and RNA

   3. Treats melanoma, and Hodgkin lymphoma

   4. Myelosuppression. Hepatotoxicity. Neurotoxicity.

4. Temozolomide

   1. Must undergo biotransformation to it’s active form MTIC.

   2. Dacarbazine, but with the ability to penetrate the CNS, and the ability to wreck DNA AND the DNA repair machinery

   3. Available orally and parenterally

5. Procarbazine (not popular for adverse reactions)

   1. Inhibits DNA, RNA and protein synthesis. Alkylates DNA after liver activation

   2. Excellent CNS penetration, especially after oral administration.

   3. Excreted renally.

   4. Causes HYPERTENSIVE CRISIS. Mutagenic and Teratogenic. Creates disulfiram-like reactions, creating a strong dislike for alcohol, even in things like mouthwash and toothpaste.

6. Busulfan

   1. Causes pulmonary fibrosis

Microtubule Modulators

-Interfere with the mitotic spindle, essential for cell division

-^This makes them all Cell Cycle Specific

-Most of these start with “Vin-” or end with “-taxel”

1. Vinca Alkaloids (used mainly for lymphoma)

   1. Vincristine (VX) is the most important; causes mild myelosuppression and used in R-CHOP.

   2. Vinblastine (VBL) is used with bleomycin and cisplatin to treat testicular cancer. Can cause myelosuppression.

   3. Vinorelbine (VRB) is used for breast cancer and advanced non-small cell lung cancer. Causes peripheral neuropathy

   4. Mechanisms of Action

      1. Block mitosis by blocking tubulin polymerization and chromosomal segregation.

   5. All the Vinca Alkaloids are delivered via IV, and metabolized/eliminated hepatically

   6. Incredibly CYTOTOXIC and contraindicated intrathecally.

2. Taxanes (Paclitaxel and Docetaxel)

   1. Promotes tubulin polymerization and stabilize tubulin polymers, to the point where the cell never divides at all.

   2. Metabolized hepatically by CYP450 and eliminated biliary

   3. Neutropenia and Leukopenia. Also creates hypersensitivity reactions, so we premedicate the patient with anti-inflammatory agents.

Steroid Hormones and Associated Antagonists

-Removing hormonal stimuli from hormone dependent tumors can treat the cancer effectively.

-Most of these will cause hyperuricemia

1. Tamoxifen

   1. SERM, an Estrogen Receptor Antagonist.

   2. FIRST LINE of therapy for estrogen responsive breast cancer. Orally available!

   3. Prevents activation of receptors in breast tissue to cause growth suppression and estrogen receptor depletion

   4. Postmenopausal Symptoms; think vasomotor symptoms. Increases risk of endometrial cancer.

2. Prednisone

   1. Anti-inflammatory corticosteroid with lymphocytolytic activity (tears apart lymphocytes) and are used to induce remission with acute lymphocytic leukemia. Can cause hyperuricemia in this regard.

3. Fulvestrant and Raloxifene

   1. Fulvestrant antagonizes estrogen receptors for hormone-responsive metastatic breast cancer. Causes estrogen receptor downregulation.

   2. Raloxifene is a SERM

4. Aromatase Inhibitors

   1. Inhibits aromatase, which reduces estrogen synthesis in places outside the adrenal glands.

   2. Nonsteroidal aromatase inhibitors

      1. Anastrozole and Letrozole

         1. Do NOT predispose patients to endometrial cancer, and do not have androgenic side effects.

         2. Treats breast cancer in postmenopausal women

         3. ORALLY effective, metabolized hepatically, excreted renally

   3. Steroidal aromatase inhibitors

      1. Exemestane

         1. IRREVERSIBLE (binds permanently)

         2. ORALLY effective, widely distributed, metabolized hepatically (drug-drug interactions) and excreted renally.

         3. Postmenopausal adverse effects

5. Progestins (not very popular)

   1. Orally effective method of treating metastatic hormone-responsive breast cancer.

6. Estrogens (not popular either)

7. GnRH analogs (important) (Leuprolide, Goserelin, and Triptorelin)

   1. Replaced hormones above. These manipulate the hypothalamus and inhibit release of LH and FSH. Tumors responsive to hormone then shrink.

   2. Leuprolide treats prostatic cancer

8. Antiandrogens (Flutamide, Nilutamide, and Bicalutamide)

   1. Block androgen receptors in prostate tissue. Used to treat prostate cancer

Monoclonal Antibodies

-Target specific portions of DNA or antigens. This reduces adverse effects

1. Trastuzumab

   1. Causes congestive heart failure.

2. Rituximab

   1. Inhibits malignant B lymphocyte proliferation, and then calls T cells to exterminate the malignant cell.

   2. Tumor lysis syndrome

3. Bevacizumab

   1. Inhibits the formation of blood vessels for the tumor, depraving it of resources.

   2. First line drug for metastatic colorectal cancer

   3. Used in combination with 5-FU

4. Cetuximab and Panitumumab

   1. Inhibits cancer cell growth by binding to Epidermal Growth Factor Receptors (EGFR)

   2. Adverse reaction is acne, and this is actually a good sign

Platinum Coordination Complexes

-Cisplatin, carboplatin and oxaliplatin

-Incredibly toxic; nephrotoxcity, ototoxicity and hepatotoxicity, along with myelosuppreission

-Bind DNA tightly to itself, preventing unwinding

-Cell Cycle Nonspecific

-Poor CNS penetration

-All of these cause severe vomiting.

Topoisomerase inhibitors

-Blocks mechanisms that prep DNA for repair

-Cell Cycle Specific

Topotecan and Irinotecan

Etoposide binds to the DNA complex and prevents them from separating. Causes double strand breaks.

Tyrosine Kinase Inhibitors

-Imatinib, Dasatinib and Nilotinib

-Cancel all secondary messengers in the “kinase pocket”

-ALL available in ORAL formations

Can cause fluid retention and QT Prolongation

ERLOTINIB TREATS NON-SMALL CELL CANCER AND PANCREATIC CANCER.

sorafenib AND sunitinib ARE USED FOR RENAL CELL CANCER.

Miscellaneous Agents

Asparaginase and Pegaspargase

-Deprive cancer cells of asparagine; crucial elements for cancer cell proliferation

-Protein based and have to be delivered by injection

Interferons

-Mechanism unknown, but are biological response modifiers.

-Have to be delivered by IV

Enzalutamide

-Antiandrogen that treats prostate cancer.

-Available orally

Abiraterone Acetate

-Treats metastatic castration-resistant prostate cancer