Alkylating agents cause abnormal pairing of the DNA causing replication to not occur. These work on rapidly replicating cells, which include cancer cells and normal cells. Our fastest growing normal cells are hematopoietic cells (bone marrow) so anyone on these drugs will be anemic and unfortunately have less white blood cells. Our GI lining grows quickly and unfortunately a side effect is very severe nausea/vomiting. Our hair follicle also grows fast, so we have hair loss. Gonads grow fast as well so anyone going through chemotherapy shouldn’t plan on getting pregnant or if it’s a male, should not assume that they have healthy sperm.
The bone marrow depression happens very slowly and takes 4-6 weeks to recover. This was a huge problem, but now with the use of filgrastim this is not an issue.
- Causes Abnormal pairing of DNA strands
- Toxicities associated with rapid growing normal tissues
- hematopoetic (blood cells)
- Bone marrow depression occurs slowly and recovers in 4 to 6 weeks
- Examples of Alkylating Agents
- Mechlorethamine (Mustargen)
- Cyclophosphamide (Cytoxan)
- Chlorambucil (Leukeran)
Nitrosureas are a group of drugs that act similar to that of alkylating agents. These drugs slow down or stop enzymes that help repair DNA. Nitrosureas cross the blood brain barrier, so they are effective against CNS tumors.
- Crosses Blood Brain Barrier
- Effective against CNS tumors
- Examples of nitrosureas:
- Carmustine (BCNU)
- Lomustine (CCUN)
Cisplatin is an alkylating-like drug. It is extremely toxic to the kidneys because it is eliminated through the kidneys and as it does it damages the kidneys. One of the uses of diuretics is to protect the kidneys from nephrotoxic drugs by decreasing contact time and diluting out these drugs that damage the kidneys. This is a prime example where we have to protect the kidneys with diuretics. One of the diuretics that protected the kidneys was Mannitol. We’d also use a high ceiling loop diuretic to make sure we dilute everything out.
Cisplatin causes extensive nausea/vomiting and before we had antinausea drugs, patients would say they rather die than take this drug. We used to literally allow patients to bring marijuana into the hospital prior to chemotherapy. Nowadays that is not necessary anymore because we have marijuana derivatives they could use. But the marijuana derivatives are not even the best options anymore. We may use metoclopramide but even more effective are the 5HT3 antagonists which are super powerful antinauseant agents. They are given one dose before chemotherapy and they may need one or two more after and they’re fine.
- Extremely Toxic
- Nephrotoxicity: must use fluids and diuretics to protect kidneys
- Extensive nausea/vomiting
- Prevention includes
- marijuana derivative dronabinol (Marinol®)
- metoclopramide (Reglan®)
- 5HT-3 Antagonist: ondasetron (Zofran®), granisetron (Kytril®)
Anti tumor Antibiotics
Antitumor antibiotics are anti-neoplastic drugs that are made from micro-organisms (probably Streptomyces bacteria). Anti-neoplastic means it inhibits/prevents the growth and spread of tumors or malignant cells (“neoplastic cells”). (A neoplasm is an abnormal mass of tissue, synonymous with the term “tumor” nowadays.)
- Doxorubicin (Adriamycin) (an anthracycline antibiotic)
- Bleomycin (Blenoxane) (glycopeptide antibiotic)
- Daunomycin (Cerubidine)
- Plicamycin (Mithracin)
This is a chemotherapy drug that’s usually used in combination and affects the bone marrow. This is a chemotherapy drug that affects the heart, accumulates there and causes permanent damage to the heart. We have to keep a record of the cumulative dose the patient has had. Once the patient has reached the maximum amount of this dose, they cannot use it anymore otherwise they’ll go into heart failure.
- Bone marrow aplasia (failure)
- Delayed cardiotoxicity leading to CHF
- Cannot exceed maximum cumulative lifetime dose
This is an interesting drug that’s used in combination with others. It’s interesting because it affects the lining of the lungs (inflammation; pneumonitis) and not the bone marrow.
- Used in combination
- Minimal effect on bone marrow
An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolates that interfere with the use of folic acid. The presence of antimetabolites can have toxic effects on cells, such as halting cell growth and cell division, so these compounds are used as chemotherapy for cancer.
- Methotrexate (Mexate)
- 6-Mercaptopurine (Purinethol)
- Azathioprine (Imuran)
- 5-Fluorouracil (Fluorouracil)
- Cytosine Arabinoside (Cytosar)
Methotrexate is an antimetabolite and antifolate drug. We briefly mentioned the use of methotrexate and other chemotherapy drugs for Rheumatoid Arthritis (in low doses) since they suppress the immune system. For chemotherapy, we use high doses. This kills cancer cells by not allowing the cells to convert folic acid to tetrahydrofolate (folinic acid). Because of these high doses, unfortunately the patient will have megaloblastic anemia and we will start having a major affect on the normal cells. Since cancer cells grow fast, it will kill a lot of cancer cells but also kill a lot of normal cells and to save the normal cells we give the leucovorin rescue. Unfortunately, this also rescues the remaining cancer cells.
- Interferes with activiation of folic acid to tetrahydrofolate
- May require leucovorin rescue
Hormonal therapy is not curative but palliative meaning it hopefully stops or slows the progression/spreading of the disease. Estrogens can be used with cancers that are stimulated by testosterone such as prostate and testicular cancers. For cancers that are caused by or sensitive to estrogen, we can’t give testosterone to females because the male side effects makes them worse off. So instead, we give anti-estrogens which we’ll talk about in detail below. And finally, in the case of uterine cancer, we use progesterone.
- Palliative therapy (not curative)
- First line therapy (less toxic than chemo)
- Sex Hormone Therapy
- Estrogens: Treatment of testosterone sensitive tumors
- Example: Diethylstilbestrol (DES)
- Testosterone and Anti-Estrogen: Treatment of estrogen sensitive tumors
- Progesterone: Treatment of uterine cancers
- Example: Medroxyprogesterone (Provera)
- Estrogens: Treatment of testosterone sensitive tumors
Since we can’t use testosterone in women, we use an anti-estrogen. Anti-estrogen drugs block the estrogen receptor, useful for any estrogen-sensitive disease such as breast cancer. An example of this drug would be tamoxifen (Nolvadex) and anastrozole (Arimidex).
- Palliative therapy of breast cancer
- Prevention of breast cancer
- Possible adverse reaction of uterine cancer
These are anti-hormonal drugs that would be used in the case of cancers that are hormonally stimulated:
- Tamoxifen (Nolvadex)
- Anastrozole (Arimidex)
- Flutamide (Eulexin)
- Bicalutamide (Casodex)
- Leuprolide (Lupron)
- Goserelin (Zoladex)
- Mitotane (Lysodren)
Corticosteroids all lower the WBC count (specifically lymphocytes) so it is useful for lymphomas and lymphocytic anemias where the immune system is going haywire. Since corticosteroids don’t kill cancer cells, this is only going to be used adjunctly with the chemotherapy drugs that kill the cancer cells.
- Adjunct therapy
- Prednisone (Orasone)
- Dexamethasone (Decadron)
- Vincristine (Oncovin)
- Vinblastine (Velban)
This is an interesting drug as well because it doesn’t affect the bone marrow but rather the neurologic system causing numbness and weakness. So we add this drug onto other drugs that do affect the bone marrow so we don’t bombard the bone marrow.
- Used in combination
- Neurologic numbness and weakness
- Minimal effects on bone marrow
Immunoadjuvant drugs help stimulate the immune system.
One of our goals is to get the tumor down from 10^12 to 10^6 cells (1 trillion to 1 million), and get the immune system working to finish the job, so that maybe we could go into remission. What percent of the population will have at least 1 cancer in the body? 100%. Not all of us have cancer because our immune system recognizes it and destroys it. The reason cancer goes haywire is because the immune system didn’t recognize it and destroy it.
Levamisole is used when a person has GI cancer to help stimulate the immune system.
BCG Vaccine: This is the tuberculosis vaccine but it’s not used as a tuberculosis vaccine in this country. This is used to stimulate the immune system against bladder cancer.
Interferons: These are naturally occurring in the body. These are antiviral chemicals. So whats this have to do with cancer? If we take a look at some of the cancers we know about, there is an association between viruses and cancer. Patients who have AIDS are prone to Kaposi’s sarcoma. The Burkitt’s virus definitely has an association with Burkitt’s lymphoma. Hepatitis viruses definitely have an association with hepatic cancers. So we definitely know there some association. There may be a lot more associations that we don’t know yet between viruses and cancer. We’ve identified a few interferons in our body (there may be hundreds of them) and they’re used as immunoadjuvant drugs against certain types of leukemia.
Laetrile? These drugs were a worthless fad people would drive to mexico to get. It was a product that was made from apricot pits. Never go into the seeds of an apricot pit. When you swallow it, it gets in your body and gets converted to cyanide. It’ll kill cancer cells and kill you too.