cyclophosphamide

Key Terms: Antineoplastic.

Definition

Cyclophosphamide is an anticancer (antineoplastic) agent. It also acts as a suppressor of the immune system. It is available under the brand names Cytoxan and Neosar.

Purpose

Cyclophosphamide is approved by the Food and Drug Administration (FDA) to treat several forms of cancer. These include:

• breast cancer
• leukemia
• malignant lymphoma
• multiple myeloma
• ovarian cancer
• soft tissue sarcoma
• mycosis fungoides
• nephrotic syndrome
• neuroblastoma
• Wilms' tumor
• retinoblastoma

Cyclophosphamide has activity against a wide variety of other cancers and conditions not specifically approved by the FDA, and patients should be aware that it may be commonly prescribed for these other disease states:

• bone cancer
• cervical cancer
• endometrial cancer
• germ cell tumors
• gestational trophoblastic tumors
• histiocytosis X
• lung cancer
• prostate cancer
• testicular cancer
• Wilms' tumor

Description

Cyclophosphamide chemically interferes with the synthesis of the genetic material (DNA and RNA) of cancer cells by cross-linking DNA strands, preventing these cells from being able to reproduce and continue the growth of the cancer.

Recommended Dosage

Cyclophosphamide may be taken either orally (in pill form) or as an injection into the vein. The dosage prescribed may vary widely depending on the patient, the cancer being treated, and whether or not other medications are also being taken.

A typical oral dosage for adults is 1 to 5 mg per kg of body weight per day for initial and maintenance dose, or 400 to 1000 milligrams per squared meter of body surface area for four to five days every three to four weeks. A typical dosage by injection is 40 to 50 mg per kg, divided in several smaller doses, for two to five days. The dose for patients receiving bone marrow transplant may be as high as 60 mg per kg per day for two days.

Precautions

Cyclophosphamide should be taken on an empty stomach. If stomach irritation occurs, it should be taken with small amounts of food or milk. Cyclophosphamide should always be taken with plenty of fluids.

Cyclophosphamide can cause an allergic reaction in some people. Patients with a prior allergic reaction to cyclophosphamide should not receive this drug.

Cyclophosphamide can cause serious birth defects if either the man or the woman is taking this drug at the time of conception or if the woman is taking this drug during pregnancy. Contraceptive measures should be taken by both men and women while on this drug. Sterility is a common side effect of cyclophosphamide. This sterility is dependent upon the dose, duration of therapy, and state of function of the ovary or testicle at the time of administration of the drug. The sterility may be irreversible in some patients.

Because cyclophosphamide is easily passed from mother to child through breast milk, breast feeding is not recommended while under treatment.

Cyclophosphamide suppresses the immune system and interferes with the normal functioning of certain organs and tissues, and its excretion from the body is dependent on a normal functioning kidney and liver. For these reasons, it is important that the prescribing physician is aware of any of the following pre-existing medical conditions:

• a current case of, or recent exposure to, chicken pox
• herpes zoster (shingles)
• all current infections
• kidney disease
• liver disease
• a prior removal of one, or both, adrenal gland(s)

Also, because cyclophosphamide is such a potent immunosuppressant, patients taking this drug must exercise extreme caution to avoid contracting any new infections.

Side Effects

Inflammation and irritation of the bladder, causing blood in the urine, is a common and severe side effect of cyclophosphamide. However, this side effect can be prevented and controlled with the administration of vigorous hydration with intravenous fluids before, during, and after chemotherapy. Patients should urinate frequently (at least every 2 hours) to enhance removal of the drug from the body, drink 3 to 4 liters of fluids a day while taking the drug by mouth and for 2 to 3 days after discontinuation of the drug unless otherwise instructed by the physician. Patients who are taking cyclophosphamide orally should avoid taking the drug at night so that they can go to the bathroom frequently during the day. The bladder-protectant drug mesna is usually administered if the patient is receiving more than 2,000 mg per square meter of body surface area of the cyclophosphamide. Another common side effect of cyclophosphamide is increased susceptibility to infection due to decreased production of cells that fight infection. Increased risk of bleeding can occur due to decrease of platelets, which are involved with the clotting process. Decreased production of red blood cells can cause anemia and patients may experience fatigue, and shortness of breath.

Nausea and vomiting can occur, usually at the higher doses. Taking the appropriate antiemetics prescribed by the physician can prevent this side effect. Temporary hair loss (alopecia) usually begins three to six weeks after the start of therapy, but hair will regrow (although it may be a different color and/or texture). Sterility can occur in both men and women, and some women may also experience stoppage of menstruation. Diarrhea and ulcers of the mouth are also possible side effects of cyclophosphamide treatment.

Less common side effects include:

• nasal stuffiness
• runny eyes
• runny nose
• sinus congestion
• dizziness
• darkening of skin or fingernails
• skin rash
• sneezing (if the drug is given too rapidly by injection into the vein
• facial flushing

Some patients may also develop a second cancer years later with cyclophosphamide therapy alone or in combination with other anti cancer drugs. Patients should discuss this side effect with their physicians and determine the risks versus the benefits of this drug for treatment of the immediate cancer.

A doctor should be consulted immediately if the patient experiences any of the following:

• painful or difficult urination
• increase in frequency or feeling of urgency to urinate
• blood in the urine
• shortness of breath
• signs of infection such as cough, sore throat, fever and chills
• pain in the lower back or sides
• unusual bleeding or bruising
• blood in the stool
• tiny red dots on the skin
• delayed healing of any wounds
• skin rash
• yellowing of the skin or eyes

Interactions

Cyclophosphamide should not be taken in combination with any prescription drug, over-the-counter drug, or herbal remedy without prior consultation with a physician.

—Paul A. Johnson, Ed.M.

trade names: Cytoxan, Neosar, Procytox; drug class: antineoplastic alkylating agent; action: alkylates DNA, RNA; inhibits enzymes that allow synthesis of amino acids in proteins; uses: Hodg-kin’s disease; lymphomas; leukemia; cancer of female reproductive tract, lung, prostate; multiple myeloma; neuroblastoma; retinoblastoma; Ew-ing’s sarcoma.

Brand names: Cytoxan®Neosar®

Chemical formula:

Drug Forms:
• Cyclophosphamide Solution for injection (below)
• Cyclophosphamide Oral tablet

Español:
• Ciclofosfamida, Solución para inyección
• Ciclofosfamida, Tableta oral

Cyclophosphamide Solution for injection

What is this medicine?

CYCLOPHOSPHAMIDE (sye kloe FOSS fa mide) is a chemotherapy drug. It slows the growth of cancer cells. This medicine is used to treat many types of cancer like lymphoma, myeloma, leukemia, breast cancer, and ovarian cancer, to name a few. It is also used to treat nephrotic syndrome in children.
 
This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
•blood disorders
•history of other chemotherapy
•history of radiation therapy
•infection
•kidney disease
•liver disease
•tumors in the bone marrow
•an unusual or allergic reaction to cyclophosphamide, other chemotherapy, other medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding

How should I use this medicine?

This drug is usually given as an injection into a vein or muscle or by infusion into a vein. It is administered in a hospital or clinic by a specially trained health care professional.

Talk to your pediatrician regarding the use of this medicine in children. While this drug may be prescribed for selected conditions, precautions do apply.

Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.

What may interact with this medicine?

Do not take this medicine with any of the following medications:
•mibefradil
•nalidixic acid

This medicine may also interact with the following medications:
•doxorubicin
•etanercept
•medicines to increase blood counts like filgrastim, pegfilgrastim, sargramostim
•medicines that block muscle or nerve pain
•St. John's Wort
•phenobarbital
•succinylcholine chloride
•trastuzumab
•vaccines

Talk to your doctor or health care professional before taking any of these medicines:
•acetaminophen
•aspirin
•ibuprofen
•ketoprofen
•naproxen

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

What should I watch for while using this medicine?

Visit your doctor for checks on your progress. This drug may make you feel generally unwell. This is not uncommon, as chemotherapy can affect healthy cells as well as cancer cells. Report any side effects. Continue your course of treatment even though you feel ill unless your doctor tells you to stop.

Drink water or other fluids as directed. Urinate often, even at night.

In some cases, you may be given additional medicines to help with side effects. Follow all directions for their use.

Call your doctor or health care professional for advice if you get a fever, chills or sore throat, or other symptoms of a cold or flu. Do not treat yourself. This drug decreases your body's ability to fight infections. Try to avoid being around people who are sick.

This medicine may increase your risk to bruise or bleed. Call your doctor or health care professional if you notice any unusual bleeding.

Be careful brushing and flossing your teeth or using a toothpick because you may get an infection or bleed more easily. If you have any dental work done, tell your dentist you are receiving this medicine.

Avoid taking products that contain aspirin, acetaminophen, ibuprofen, naproxen, or ketoprofen unless instructed by your doctor. These medicines may hide a fever.

Do not become pregnant while taking this medicine. Women should inform their doctor if they wish to become pregnant or think they might be pregnant. There is a potential for serious side effects to an unborn child. Talk to your health care professional or pharmacist for more information. Do not breast-feed an infant while taking this medicine.

Men should inform their doctor if they wish to father a child. This medicine may lower sperm counts.

If you are going to have surgery, tell your doctor or health care professional that you have taken this medicine.

What side effects may I notice from receiving this medicine?

Side effects that you should report to your doctor or health care professional as soon as possible:
•allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
•low blood counts - this medicine may decrease the number of white blood cells, red blood cells and platelets. You may be at increased risk for infections and bleeding.
•signs of infection - fever or chills, cough, sore throat, pain or difficulty passing urine
•signs of decreased platelets or bleeding - bruising, pinpoint red spots on the skin, black, tarry stools, blood in the urine
•signs of decreased red blood cells - unusually weak or tired, fainting spells, lightheadedness
•breathing problems
•dark urine
•mouth sores
•pain, swelling, redness at site where injected
•swelling of the ankles, feet, hands
•trouble passing urine or change in the amount of urine
•weight gain
•yellowing of the eyes or skin

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
•changes in nail or skin color
•diarrhea
•hair loss
•loss of appetite
•missed menstrual periods
•nausea, vomiting
•stomach pain

This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Where should I keep my medicine?

This drug is given in a hospital or clinic and will not be stored at home.

Last updated: 7/1/2002

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

A neoplastic suppressant used in the treatment of lymphomas and leukemias.

Cyclophosphamide

Systematic (IUPAC) name
N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide
Identifiers
CAS number	50-18-0
ATC code	L01AA01
PubChem	2907
DrugBank	APRD00408
ChemSpider	2804
Chemical data
Formula	C7H15Cl2N2O2P
Mol. mass	261.086 g/mol
SMILES	eMolecules & PubChem
Physical data
Melt. point	2 °C (36 °F)
Pharmacokinetic data
Bioavailability	>75% (oral)
Protein binding	>60%
Metabolism	Hepatic
Half life	3-12 hours
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	D(AU) D(US)
Legal status	℞ Prescription only
Routes	Oral, intravenous
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Cyclophosphamide (the generic name for Endoxan, Cytoxan, Neosar, Procytox, Revimmune), also known as cytophosphane, is a nitrogen mustard alkylating agent,^[1] from the oxazophorines group.

An alkylating agent adds an alkyl group (C_nH_2n+1) to DNA. It attaches the alkyl group to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring.

It is used to treat various types of cancer and some autoimmune disorders. It is a "prodrug"; it is converted in the liver to active forms that have chemotherapeutic activity.

Contents 1 Uses 2 Pharmacokinetics/Pharmacodynamics 3 Mode of action 4 Side-effects 5 History 6 References

Uses

The main use of cyclophosphamide is together with other chemotherapy agents in the treatment of lymphomas, some forms of leukemia^[2] and some solid tumors^[3]. It is a chemotherapy drug that works by slowing or stopping cell growth.

Cyclophosphamide also decreases the immune system's response to various diseases and conditions. Therefore, it has been used in various non-neoplastic autoimmune diseases where disease-modifying antirheumatic drugs (DMARDs) have been ineffective. For example, systemic lupus erythematosus (SLE) with severe lupus nephritis^[4] may respond to pulsed cyclophosphamide (in 2005, however, standard treatment for lupus nephritis changed to mycophenolic acid (MMF) from cyclophosphamide). Cyclophosphamide is also used to treat Minimal Change Disease, severe rheumatoid arthritis^[5], Wegener's granulomatosis^[6] (with trade name Cytoxan), and multiple sclerosis^[7] (with trade name Revimmune).

However, a 2004 study^[8] showed that the biological actions of cyclophosphamide are dose-dependent. At high doses, it is immunosuppressant, while at low continuous dosage it shows immunostimulatory and antiangiogenic properties. A 2009 study of 17 patients with docetaxel-resistant metastatic hormone refractory prostate cancer showed a Prostate-specific antigen (PSA) decrease in 9 of the 17 patients, and concluded that low-dose cyclophosphamide "is an interesting candidate for combination therapies, e.g., immunotherapy, tyrosine kinase inhibitors, and antiangiogenisis."^[9]

Pharmacokinetics/Pharmacodynamics

Cyclophosphamide is converted by mixed function oxidase enzymes in the liver to active metabolites^[10]. The main active metabolite is 4-hydroxycyclophosphamide, which exists in equilibrium with its tautomer, aldophosphamide. Most of the aldophosphamide is oxidised by the enzyme aldehyde dehydrogenase (ALDH) to make carboxyphosphamide. A small proportion of aldophosphamide is converted into phosphoramide mustard and acrolein. Acrolein is toxic to the bladder epithelium and can lead to hemorrhagic cystitis. This can be prevented through the use of aggressive hydration and/or Mesna.

Recent clinical studies have shown that cyclophosphamide induce beneficial immunomodulatory effects in the context of adoptive immunotherapy. Although the mechanisms underlying these effects are not fully understood, several mechanisms have been suggested based on potential modulation of the host environment, including^{[citation needed]}:

1. Elimination of T regulatory cells (CD4+CD25+ T cells) in naive and tumor-bearing hosts
2. Induction of T cell growth factors such as type I IFNs, and/or
3. Enhanced grafting of adoptively transferred tumor-reactive effector T cells by the creation of an immunologic space niche.

Thus, cyclophosphamide pre-conditioning of recipient hosts (for donor T cells) has been used to enhance immunity in naïve hosts, and to enhance adoptive T cell immunotherapy regimens as well as active vaccination strategies, inducing objective anti-tumor immunity.

Mode of action

The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard. This metabolite is only formed in cells that have low levels of ALDH.

Phosphoramide mustard forms DNA crosslinks between (interstrand crosslinkages) and within (intrastrand crosslinkages) DNA strands at guanine N-7 positions. This leads to cell death.

Cyclophosphamide has relatively little typical chemotherapy toxicity as ALDHs are present in relatively large concentrations in bone marrow stem cells, liver and intestinal epithelium. ALDHs protect these actively proliferating tissues against toxic effects phosphoramide mustard and acrolein by converting aldophosphamide to carboxyphosphamide that does not give rise to the toxic metabolites (phosphoramide mustard and acrolein).

Side-effects

Many people taking cyclophosphamide do not have serious side effects. Side-effects include chemotherapy-induced nausea and vomiting (CINV), bone marrow suppression, stomach ache, diarrhea, darkening of the skin/nails, alopecia (hair loss) or thinning of hair, changes in color and texture of the hair, and lethargy. Hemorrhagic cystitis is a frequent complication, but this is prevented by adequate fluid intake and Mesna (sodium 2-mercaptoethane sulfonate). Mesna is a sulfhydryl donor and binds acrolein.

Cyclophosphamide is itself carcinogenic, potentially causing transitional cell carcinoma of the bladder as a long-term complication. It can lower the body's ability to fight an infection. It can cause temporary or (rarely) permanent sterility. Although it is used to treat cancer, it may increase the risk of developing another form of cancer, sometimes months to years after treatment.

Other (serious) side effects include:

• pink/bloody urine,
• unusual decrease in the amount of urine,
• mouth sores,
• unusual tiredness or weakness,
• joint pain,
• easy bruising/bleeding,
• existing wounds that are slow healing.

History

Cyclophosphamide and the related nitrogen mustard-derived alkylating agent ifosfamide were developed by Norbert Brock and ASTA (now Baxter Oncology). Brock and his team synthesised and screened more than 1,000 candidate oxazaphosphorine compounds.^[11] They converted the base nitrogen mustard into a non-toxic "transport form". This transport form was a pro-drug, subsequently actively transported into the cancer cells. Once in the cells, the pro-drug was enzymatically converted into the active, toxic form. The first clinical trials were published at the end of the 1950s.^[12][13][14]

References

1. ^ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
2. ^ Shanafelt TD, Lin T, Geyer SM, et al. (June 2007). "Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia". Cancer 109 (11): 2291–8. doi:10.1002/cncr.22662. PMID 17514743. 
3. ^ Young SD, Whissell M, Noble JC, et al. (2006). "Phase II clinical trial results involving treatment with low-dose daily oral cyclophosphamide, weekly vinblastine, and rofecoxib in patients with advanced solid tumors". Clinical Cancer Research 12 (10): 3092-8. PMID 16707607. 
4. ^ Steinberg AD, Kaltreider HB, Staples PJ, et al. (August 1971). "Cyclophosphamide in lupus nephritis: a controlled trial". Annals of Internal Medicine 75 (2): 165-71. PMID 4104337. 
5. ^ Townes AS, Sowa JM, Shulman LE (May-June 1976). "Controlled trial of cyclophosphamide in rheumatoid arthritis". Arthritis & Rheumatism 19 (3): 563-73. PMID 779796. 
6. ^ Novack SN, Pearson CM. (April 1971). "Cyclophosphamide therapy in Wegener's granulomatosis". New England Journal of Medicine 284 (17): 938-42. PMID 5551803. 
7. ^ Makhani N, Gorman MP, Branson HM, et al. (June 2009). "Cyclophosphamide therapy in pediatric multiple sclerosis". Neurology volume=72 (24): 2076-82. PMID 19439723. 
8. ^ Nicolini A, Mancini P, Ferrari P, et al (2004). "Oral dose cyclophosphamide in metastatic hormone refractory prostate cancer (MHRPC).". Biomed Parmacother. 58: 447-50. 
9. ^ Nelius T, Klatte T, et al (April 2009). "Clinical outcome of patients with docetaxel-resistant hormone-refractory prostate cancer treated with second-line cyclophosphamide-based metronomic chemotherapy". Medical Oncology (Humana Press Inc.). doi:10.1007/s12032-009-9218-8. ISSN (Print) 1559-131X (Online) 1357-0560 (Print) 1559-131X (Online).  [1]
10. ^ Cohen JL, Jao JY (1970). "Enzymatic basis of cyclophosphamide activation by hepatic microsomes of the rat.". Journal of Pharmacology And Experimental Therapeutics 174 (2): 206-10. PMID 4393764. 
11. ^ Brock N (1996). "The history of the oxazaphosphorine cytostatics". Cancer 78 (3): 542–7. doi:10.1002/(SICI)1097-0142(19960801)78:3<542::AID-CNCR23>3.0.CO;2-Y. PMID 8697402. 
12. ^ Wilmanns, H. (1958). Asta-Forschung und Therapie. 
13. ^ Gross, R., and Wulf, G. (1959). "Klinische und experimentelle Erfahrungen mit zyk lischen und nichtzyklischen Phosphamidestern des N-Losl in der Chemotherapie von Tumoren". Strahlentherapie 41 (Sonderband III): 361–367. 
14. ^ Brock N (1989). "Oxazaphosphorine cytostatics: past-present-future. Seventh Cain Memorial Award lecture" (PDF). Cancer Res. 49 (1): 1–7. PMID 2491747. http://cancerres.aacrjournals.org/cgi/reprint/49/1/1. 

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