February 15, 2013

Today, we will be discussing the definition of chemotherapy and the different types of chemotherapy for cancer eradication.  We will also look at some other methods for eradicating cancer that can be less harmful than chemotherapy.

• Chemotherapy

1.      Although the word chemotherapy can mean the use of any drug (such as aspirin or penicillin) to treat any disease, to most people chemotherapy refers to drugs used for cancer treatment.

2.      Two other medical terms often used to describe cancer chemotherapy are antineoplastic (meaning anti-cancer) terapy and cytotoxic (cell-killing) therapy.

• History of chemo

1.      Started as chemical warfare agents in WWI with the use of mustard gas.

2.      During WWII accidental exposure to mustard gas produced low white blood cell counts.

3.      Doctors presumed mustard gas killed WBCs, so in 1940s patients with advanced lymphomas were treated, and although the results were temporary, they showed remarkable improvement.

This next portion is going to review the standard chemotherapy treatments.

• Alkylating agents

1.      Electron-deficient drug that directly damages DNA through covalent bonds (especially guanine) and produce effects which disrupt (sometimes permanently) DNA replication and transcription which hopefully results in cell death.

2.      Alkylating agents advantages

a.       Are not phase-specific and have the ability to kill non-proliferating cells, which makes them choice drugs for tumors with low growth fractions.

b.      Have an almost infinite number of potential DNA disruption sites.

c.       They do not typically exhibit a plateau in cell survival with increasing dose.

3.      Alkylating agents disadvantages

a.       Toxic to bone marrow stem cells.

b.      Produce delayed, prolonged or even permanent bone marrow failure.

c.       Often cause irreversible infertility.

d.      Mutagenic and carcinogenic effect on bone marrow stem cells ultimately arising in acute myelogenous leukemia (AML)

4.      The Alkylating Agents

a.       Nitrogen mustards:  such as mechlorethamine (nitrogen mustard), chlorambucil, cyclophosphamide (Cytoxan®), ifosfamide, and melphalan.

b.      Nitrosoureas:  which include streptozocin, carmustine (BCNU), and lomustine.

c.       Alkyl sulfonates:  busulfan.

d.      Triazines:  dacarbazine (DTIC) and temozolomide (Temodar®)

e.       Ethylenimines:  thiotepa and altretamine (hexamethylmelamine)

• Antimetabolites

1. Interfere with DNA and RNA growth by substituting for the normal building blocks of RNA and DNA.
2. They interfere with nucleic acid synthesis, so they have little effect on G0 cells and are most damaging to cells in S-phase.
3. Antimetabolite advantages:

a.       Not associated with delayed or prolonged myelosuppresion.

b.      Present minimal risk for leukemogenesis and/or carcinogenesis.

4.   Antimetabolite disadvantage

a.       Exhibits plateau in cell survival with increasing dose.

5.      The antimetabolites

a.       5-fluorouracil (5-FU)

b.      6-mercaptopurine (6-MP)

c.       Capecitabine (Xeloda ®)

d.      Cladribine

e.       Clofarabine

f.        Cytarabine (Ara-C ®)

g.       Floxuridine

h.       Fludarabine

i.         Gemcitabine (Gemzar ®)

j.        Hydroxyurea

k.      Methotrexate

l.         Pemetrexed (Alimta ®)

m.     Pentostatin

n.       Thioguanine

• Antitumor antibiotics

1.      Structurally diverse group of compounds all derived from various species of Streptomyces.

2.      Too cytotoxic for normal antibiotic use, but they are valuable in treating a broad spectrum of tumors.

3.      Disrupts DNA replication and RNA transcription.

4.      Can produce single- and double- stranded DNA scission and impair DNA repair.

5.      Can create free radicals, which generates DNA breaks and other damage to cellular structures.

6.      Possibly kill through cell membrane disruption.

7.      Advantage:  drugs are active throughout the cell cycle, but most toxic for cells in S-phase or G2.

8.      Disadvantage:  the ability to generate free radical can lead to cardiac toxicity.

9.      The anti-tumor antibiotics

a.       Daunorubicin

b.      Doxorubicin (Adriamycin ®)

c.       Epirubicin

d.      Idarubicin

e.       Acinomycin-D

f.        Bleomycin

g.       Mitomycin-C

·        Vinca alkaloids (plant)

1.      They bind to the protein tubulin (which normally forms the apparatus along which chromosomes migrate during mitosis) and arrest the cell growth.

2.      Vincristine important for childhood ALL and in combination with other drugs for lymphomas.

3.      Vinblastine for testicular cancer.

• Etoposide (plant alkaloid)

1.      Also causes metaphase arrest and induces DNA strand breaks

2.      Key for nonseminomatous testicular cancer, non-Hodgkin’s lymphoma, and small-cell lung cancer.

• Hormone therapy

1.      Drugs in this category are sex hormones, or hormone-like drugs, that change the action or production of female or male hormones.  They are used to slow the growth of breast, prostate, and endometrial cancers.

2.      They do not work in the same ways as standard chemotherapy drugs, but rather by preventing the cancer cell from using the hormone it needs to grow, or by preventing the body from making the hormones.

·        Immunotherapy

1.      Some drugs are given to people with cancer to stimulate their natural immune systems to recognize and attack cancer cells.  These drugs offer a unique method of treatment, and are often considered to be separate from chemotherapy.

Some strategies to improve systemic cancer treatment

·        Adjuvant chemotherapy

1.      Given to destroy leftover (microscopic) cells that may be present after the known tumor is removed by surgery to prevent a possible cancer recurrence.

2.      Neoadjuvant chemotherapy:  given prior to the surgical procedure in an attempt to shrink the tumor so that the surgical procedure may not need to be as extensive.

·        Dosage intensification

1.      Followed by bone marrow transplant and facilitated by the use of hemapoietic growth factors.

• Interferons

1.      Molecules normally produced in response to viral infection, but its specific antitumor mechanism is not known.

• Induction of tumor differentiation

1.      The growth of tumors comes from failure to mature and differentiate, so researchers are attempting to find an agent that causes cells to “grow up” rather than kill them.

Reflections:

When it comes time for the registry exam, I will need to know various chemotherapy drug names and their effects on the cells of the body.  I will probably be asked what “chemotherapy” means as well.  I will be able to recall that chemotherapy is a term that can refer to any drug that is used to treat any disease, but that we use the term to define drugs given in connection with cancer killing drugs and anti-cancer drugs.

I decided to do some internet searches for immunotherapy.  I found that in 2011 an immunotherapeutic drug was allowed by the FDA to be prescribed for metastatic melanoma.  The first link I went to was at:  http://www.cancercenter.com/conventional-cancer-treatment/immunotherapy.cfm which is a link to Cancer Treatment Centers of America, which prescribes the medicine to qualifying patients.  Then, I went back to google and clicked on this link:  http://www.mskcc.org/pressroom/press/novel-immunotherapy-drug-receives-fda-approval-treatment-metastatic-melanoma which says the FDA approved usage of Ipilimumab known as Yervoy.  It apparently manipulates the T cells to attack the metastases, though it doesn't go into much detail