Chemotherapy for Histiocytosis
Disclaimer: All of these primers are written by parents that have NO medical background prior to having to deal directly with the disease. The contents should not be misinterpreted as medical advice. Our opinions could be wrong. The intent is to help you come up the learning curve and hopefully bypass some of the difficulties we have encountered. Always refer to your doctor. Like almost all things in life, there are many correct answers.Dr. Arceci's article on 'New Treatment Approaches for Patients with LCH' is an excellent starting point.
This treatment map sums up the current ways LCH is treated. Note: It is important to realize because of the relative infrequency of JXG compared to LCH, there is very little knowledge available on how to treat JXG, so typically, for lack of a better path, multi-system JXG patients are treated as if they were high risk LCH patients.
Specific Chemotherapies Used for Histiocytosis
Note: Some of these chemotherapies are used frequently for a given histiocytosis, others have only been tried on an experimental basis. I have tried to focus on how the chemo works, what it does, what else it is used for and where it came from. I have tried to avoid listing of side effects as you can find these many places. It is important to remember that the doses given for histiocytosis may be very different than the doses given for other diseases, therefore many of the side effects you see listed may not be as prevalent.Prednisone - Prednisone is just an oral form of Cortisone. It is a steroid hormone. Prednisone decreases inflammation by preventing white blood cells from functioning properly. More specifically, the drug interferes with lymphocytes (one of several types of white blood cells). The presence of white blood cells result in inflammation (for many reasons, damage to tissue, fungus, virus, bacteria, allergens and almost any foreign invader) - they go to a site and their presence inflames the area. Prednisone causes lymphocytes to break apart and die. The lesions in histiocytosis usually contain lymphocytes, so prednisone attacks the lesions. Decadron - Also called Dexamethasone - Is a much higher concentration of Corticoid than Prednisone and it is usually injected. The mechanism of action is the same as Prednisone.
Vinblastine (Velban) / Vincristine (Oncovan) - Vinblastine is a plant alkaloid and inhibits mitosis or cell division. Vinblastine disrupts cell division, resulting in cell death. Specifically, it works to inhibit mitosis (cell division) in metaphase. You can find a short history of Vinblastine here. Vinblastine is actually derived from the Madagascar Periwinkle. Vincristine is very similar to Vinblastine. Its chemical structure is just slightly different. Is is also derived form the Madagascar Periwinkle.
Methotrexate (MTX) - Methotrexate is an Antimetabolite. This medicine acts by altering the body's use of folic acid (a vitamin), which is needed for cell growth. Methotrexate is often used to treat rheumatoid arthritis, which is an immune system disorder (like the histiocytoses are suspected to be). Scientists suspect that this interference with folic acid is an important reason for methotrexate's benefit in rheumatoid arthritis. The neat thing about MTX is that the normal cells are affected, but they can give folic acid to rescue the normal cells, while the active or bad cells tend not to recover. The reason for the hospital stay is two-fold - 1) the drug takes quite awhile to administer and is difficult to handle, 2) the blood levels for Methotrexate need to be monitored and folic acid or lukivoran (both names for the same vitamin) needs to be administered after the Methotrexate is done working to 'rescue' the good cells. Leukemia patients receive over 20 times more Methotrexate than LCH patients do, so LCH patients get relatively low doses of Methotrexate.
6-Mercaptopurine (6MP) - 6MP is an Antimetabolite. 6MP is used to treat many autoimmune diseases. 6MP is cell cycle specific. In the body, 6MP is converted to thioinosinic acid by the enzyme hypoxanthine-guanine phosphoribosyltransferase. Thioinosinic acid then inhibits reactions involving inosinic acid. Also, both thioinosinic acid and 6-methylthioinosinate (also formed from mercaptopurine) inhibit RNA synthesis. RNA is a major part of the machinery involved in duplicating DNA, if RNA is not longer available, DNA is not duplicated and cells no longer multiply. This would hopefully prevent lesional cells from multiplying.
2-Chlorodeoxyadenosine (2-CdA) - Antimetabolite. 2-CdA is potently toxic to monocytes in vitro (in test tube). Because tissue histiocytes are derived from the same stem cells as circulating monocytes, 2-CdA is a logical chemotherapy. Also know as Cladribine, 2-CdA is most commonly used for hairy cell leukemia. In essence it works by impacting the synthesis of DNA in monocytes and lymphocytes. Via several steps, it breaks the DNA strands. It works on both resting and proliferating lymphocytes and monocytes - so it may even be able to reduce 'old' or inactive lesions. Cladribine can cause neutropenia (neutrophil count below 300) and that can open the door to serious infections (note this can happen with almost all chemotherapy, but seems to be a higher risk with 2-CdA) - 2-CdA really hits the bone marrow. 2-CdA can also reduce the platelet count severely.
Cytarabine (Ara-C) - Antimetabolite. Converted in the cells to another chemical called 'active cytarabine-5'-triphosphate', which inhibits DNA polymerase. Ara-C is cell-phase specific, acting in the S phase to kill cells undergoing DNA synthesis and also blocking the progression of cells from the G1 phase to the S phase. It has been around for many years and has been used successfully for leukemias and lymphomas.
L-Asparaginase (L-asp) - L-asp is classified in the 'other' category. L-asparaginase exploits the unusually high requirement tumor cells have for the amino acid “asparagine.” Asparagine is an amino acid required by cells for the production of protein. Asparagine can be produced within a cell through an enzyme called “asparagine synthetase” or it can absorbed into the cell from the outside through food. Tumor cells, more specifically lymphatic tumor cells, require huge amounts of asparagines to keep up with their rapid, malignant growth. This means they use both asparagine from the diet as well as what they can make themselves (which is limited) to satisfy their large asparagines demand. L-asparaginase is an enzyme that destroys asparagine external to the cell. Normal cells are able to make all the asparagine they need internally whereas tumor cells become depleted rapidly and die.
Thalidomide - Anigiogenesis - It is believed that Thalidomide prevents the development of new blood vessels - it also probably has several other effects that are not well understood. Thalidomide was first marketed in Europe in the late 1950's. It was used as a sleeping pill and to treat morning sickness during pregnancy. In the early 1960's thalidomide was found to cause birth defects and thousands of babies in Europe were born with sever skeletal defects.
Thalidomide's effects on the rapidly dividing cells of embryos suggested that it might squelch cancer cells too. Without blood and the nutrients and growth factors it carries, fetal development was stunted. Thalidomide's capacity to obstruct angiogenesis (blood vessel development) prompted doctors to test the drug as a treatment for cancer patients, because like a fetal limb, a tumor needs new blood vessels to grow. Drugs that inhibit the formation of blood vessels stymie tumor growth. Inside a growing ball of cancer cells, the blood supply and therefore oxygen begin to run short and the cells start to suffocate. Malignant cancers get over this problem by sending out a signal to the body to grow new arteries into the tumor - in fact this is how cancer got its name - from the characteristic crab claw arteries.
Thalidomide has really just started to be seen as a chemotherapy option in the last five years. Safety and effectiveness have not been demonstrated in pediatric patients below the age of 12. Thalidomide does not seem to be effective on solid tumors, but blood related diseases are most likely affected.
Here is a recent article on Anigiogenesis in USA Today.Etanercept (Embrel) - Embrel, like Methotrexate, is often used for for rheumatoid arthritis. Etanercept neutralizes tumor necrosis factor alpha (TNF-a). TNF-a is part of the normal immune system inflammatory response. In LCH, elevated levels of TNF-a have been reported, so it stands to reason that anti-TNF-a therapy, like Embrel, may slow, stop or reduce the progression of the disease.
Etoposide (VP16) - VP16 is classified as a Mitotic Inhibitor - VP16 or Etoposide is a semi-synthetic derivative of a plant-derived toxin (in this case the plant is podophyllum peltatum) that inhibits the protein synthesis and DNA replication of tumor cells. Etoposide blocks the cell reproduction cycle by disruption of chromosomal dynamics. Etoposide may work by impacting chromosomes and is sometimes associated with secondary cancers- see article here.
Cyclophosphamide (Cytoxan) - Alkyating Agent. Cyclophosphamide is one of a number of medications first developed as a chemotherapy drug (a medication used in the treatment of cancer). It was discovered that - in addition to its usefulness in cancer - cyclophosphamide also has a significant ability to suppress the immune system. Cytoxan is also often used to treat rheumatoid arthritis.
Doxorubicin Hydrochloride (Adriamycin) - Antiumor Antibiotics. Produced by Streptomyces peucetius. Cell-cycle specific for the S phase of cell division. Antineoplastic activity may be due to binding to DNA by intercalating between base pairs resulting in inhibition of synthesis of DNA and RNA by template disordering and steric obstruction. The liposomal product is produced with surface-bound methoxypolyethylene in order to protect liposomes from detection by mononuclear phagocytes and to increase blood circulation time. It is believed the liposomes are able to penetrate altered and often compromised vasculature of tumors.
Temozolomide (Temodar) - Oral cytotoxic alkylating agent. Themozolomide is the lead compound in a new class of compounds known as imidazotetrazines. The mechanism of action of Temodar is complex and involves more than one site of action. In certain cancer cells, temodar has been shown to have an inhibitory action on certian enzymes. However, the main cytotoxic (cell-killing) action of temodar is effected by its role as an alkylating (or methylating) agent, specifically the alkylation of DNA.
Experimental - While many of the drugs listed above are still considered experiment for Histiocytosis, others are even more experimental. Some of these drugs are worth considering, but they have not been studied sufficiently enough with respect to Histiocytosis. They are Deoxycoformycin - similar to 2Cd, Interleukin-2, Cycloporin, FK-506, & retinoic acid (Vitamin A).
Metronomic - Low dose chemotherapy. Remember the metronome on top of the piano slowly clicking time? The ideas is to give consistent (lower) doses of a drug instead of the high doses for short times and then wait for recovery (typical chemo). This may be more effective than the high dose then wait concept because you remove any period when cells can start multiplying again - you do not have a time period when the chemo is no longer present and therefore no longer working.
Biphosphanates, wich are potent inhibtors of bone resorption, has been shown to reduce the incidence of skeletal events, prevent hypercalcemia, alleviate bone pain and improve the patient`s quality of life , contributing to the long-term control of bone disease.
Types of Chemotherapies
Even though there are around a hundred chemotherapies, they can be categorized by how they work.
1) Alkylating Agents or Alkylators - kill cancer cells by directly attacking DNA, the genetic material of the genes. Click here for info on the way they were discovered.
2) Nitrosureas - work by inhibiting the changes necessary for DNA repair. A very important feature of this class of drugs is that they can cross the blood-brain barrier which makes them very useful for treating brain tumors.
3) Antimetabolites or Folic Acid Antagonists - interfere with the production of DNA & RNA (with out RNA, DNA production is impacted) and keep cells from growing and multiplying.
4) Antitumor Antibiotics- are made from natural substances such as fungi in the soil. They interfere with important cell functions, including production of DNA and cell proteins. Click here for info on the way they were discovered.
5) Mitotic Inhibitors, Antimoiotic Agents or Plant Alkaloids - prevent cells from dividing normally
6) Corticosteroid Hormones or Steroid Hormones - slow the growth of some cancers that depend on hormones. Click here for info on the way they were discovered.
7) Sex Hormones - Slow down the growth of certain tumors.
8) Immunotherapy Drugs - drugs that help stimulate the immune system to more effectively recognize and attack cancer cells
9) Inorganics - Cisplatin, derived from Platinum is the most well known case of this.
10) Angiogenesis - Drugs that work by preventing the formation of blood vessels. Tumors need a supply of blood to continue to grow, therefore they build new blood vessels.
Others...For additional detail see:
ACS - How does Chemotherapy Work?
ACS - What Are the Different Types of Chemotherapy Drugs?
Oral Cancer Foundation - Chemotherapy
Breastcancer.org - Classes of Drugs
Magic Bullets Cancer vs. Chemistry