Antineoplastic Drug

Vincristine (brand name, Oncovin), formally known as leurocristine, sometimes abbreviated "VCR",
is a vinca alkaloid from the Catharanthus roseus (Madagascar periwinkle), formerly Vinca rosea and hence its name. It is a mitotic inhibitor, and is used in cancer chemotherapy. Tubulin is a structural protein that polymerizes to microtubules. The cell cytoskeleton and mitotic spindle, among other things, are made of microtubules. Vincristine binds to tubulin dimers, inhibiting assembly of microtubule structures. Disruption of the microtubules arrests mitosis in metaphase. Therefore, the vinca alkaloids affect all rapidly dividing cell types including cancer cells, but also those of intestinal epithelium and bone marrow.

Use
Vincristine is delivered via intravenous infusion for use in various types of chemotherapy regimens. Its main uses are in non-Hodgkin's lymphoma as part of the chemotherapy regimen CHOP, Hodgkin's lymphoma as part of MOPP, COPP, BEACOPP, or the less popular Stanford V chemotherapy regimen, in acute lymphoblastic leukemia, and in treatment for nephroblastoma (Wilms tumor, a kidney tumor most common in young children). It is also used to induce remission in ALL with Dexamethasone and LAsparaginase. Vincristine is occasionally used as an immunosuppressant, for example, in treating thrombotic thrombocytopenic purpura (TTP) or chronic idiopathic thrombocytopenic purpura (ITP). It is used in combination with prednisone to treat childhood leukemia.

Side-effects
The main side-effects of vincristine are peripheral neuropathy, hyponatremia, constipation, and hair loss. Peripheral neuropathy can be severe, and hence a reason to avoid, reduce, or stop the use of vincristine. One of the first symptoms of peripheral neuropathy is foot drop: A person with a family history of foot drop and/or Charcot-Marie-Tooth disease (CMT) may benefit from genetic testing for CMT before taking vincristine.Accidental injection of vinca alkaloids into the spinal canal (intrathecal administration) is highly dangerous, with a mortality rate approaching 100 percent. The medical literature documents cases of ascending paralysis due to massive encephalopathy and spinal nerve demyelination, accompanied by intractable pain, almost uniformly leading to death; a handful of survivors were left with devastating neurological damage with no hope of recovery. Rescue treatments consist of washout of the cerebrospinal fluid and administration of protective medications] A significant series of inadvertent intrathecal vincristine administration occurred in China in 2007 when batches of cytarabine and methotrexate (both often used intrathecally) manufactured by the company Shanghai Hualian were found to be contaminated with vincristine

Doxorubicin (INN, pronounced /dksrubsn/; trade name Adriamycin; also known

as hydroxydaunorubicin) is a drug used in cancerchemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works byintercalating DNA. Doxorubicin is commonly used in the treatment of a wide range of cancers, including hematological malignancies, many types of carcinoma, and soft tissue sarcomas. Doxorubicin's most serious adverse effect is life-threatening heart damage.

The drug is administered intravenously, in the form of hydrochloride salt. It may be sold under the brand names Adriamycin PFS,Adriamycin RDF, or Rubex.
[2]

Doxorubicin is photosensitive, and containers

are often covered by an aluminum bag and/or brown wax paper to prevent light from affecting it. The molecule was originally isolated in the 1950s from bacteria found in soil samples taken from Castel del Monte, an Italian castle.

History
The history of doxorubicin can be traced back to the 1950s, when an Italian research company, Farmitalia Research Laboratories, began an organized effort to find anticancer compounds from soilbased microbes. A soil sample was isolated from the area surrounding the Castel del Monte, a 13th century castle. A new strain of Streptomyces peucetius, which produced a red pigment, was isolated, and an antibiotic was produced from this bacterium that was found to have good activity against murine tumors. Since a group of French researchers discovered the same compound at about the same time, the two teams named the compound daunorubicin, combining the name Dauni, a pre-Roman tribe that occupied the area of Italy where the compound was isolated, with the French word for ruby, rubis, describing the color. Clinical trials began in the 1960s, and the drug saw success in treating acute leukemia and lymphoma. However, by 1967, it was recognized that daunorubicin could produce fatal cardiac toxicity. Researchers at Farmitalia soon discovered that changes in biological activity could be made by minor changes in the structure of the compound. A strain of Streptomyces was mutated using N-nitroso-Nmethyl urethane, and this new strain produced a different, red-colored antibiotic. They named this new compound Adriamycin, after the Adriatic Sea, and the name was later changed to doxorubicin to conform to the established naming convention.
[5]

Doxorubicin showed better activity than daunorubicin against

murine tumors, and especially solid tumors. It also showed a higher therapeutic index, yet the cardiotoxicity remained. Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines. Subsequent research by many investigators throughout the world has led to many other anthracycline antibiotics, or analogs, and it is now estimated that there are over 2,000 known analogs of doxorubicin. By 1991, 553 of them had been evaluated in the screening program at the National Cancer Institute(NCI).

Clinical use
Doxorubicin is commonly used to treat some leukemias and Hodgkin's lymphoma, as well as cancers of the bladder, breast, stomach, lung, ovaries, thyroid, soft tissue sarcoma,multiple myeloma, and others. Commonly used doxorubicin-containing regimens are AC (Adriamycin, cyclophosphamide), TAC (Taxotere,
[2]

CA), ABVD (Adriamycin, bleomycin,vinblastine, dacarbazine), BEACOPP, CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) and FAC (5-fluorouracil, Adriamycin, cyclophosphamide). Doxil (see below) is used primarily for the treatment of ovarian cancer where the disease has progressed or recurred after platinum-based chemotherapy, or for the treatment of AIDS-related Kaposi's sarcoma.
[7]

Ifosfamide is often used in conjunction with Mesna to avoid internal bleeding in the patient, in particular hemorrhagic cystitis. Ifosfamide is given quickly, and in some cases can be given in as little as an hour.

Chlorambucil
Chlorambucil (marketed as Leukeran by GlaxoSmithKline) is a chemotherapy drug that has been mainly used in the treatment of chronic lymphocytic leukemia. It is a nitrogen mustard alkylating agent[1] and can be given orally. In the past, chlorambucil has been used for treating some types of non-Hodgkin lymphoma, Waldenstrm macroglobulinemia, polycythemia vera, trophoblastic neoplasms, and ovarian carcinoma. It also has been used as an immunosuppressive drug for various autoimmune and inflammatory conditions, such as nephrotic syndrome. Its current use is mainly in chronic lymphocytic leukemia, as it is well tolerated by most patients, though chlorambucil has been largely replaced by fludarabine as first-line treatment in younger patients.[2]

Side Effects
Bone marrow suppression (anemia, neutropenia, thrombocytopenia) is the most commonly occurring side effect of chlorambucil. Withdrawn from the drug, this side effect is typically reversible. Like many alkylating agents, chlorambucil has been associated with the development of other forms of cancer. Less commonly occurring side effects include:

Gastrointestinal Distress (nausea, vomiting, diarrhea, and oral ulcerations).

Central Nervous System: Seizures, tremors, muscular twitching, confusion, agitation, ataxia, and hallucinations.

Skin reactions Hepatotoxicity Infertility

Prednisone is a synthetic corticosteroid drug that is particularly effective as

an immunosuppressant drug. It is used to treat certain inflammatory diseases and (at higher doses) some types of cancer, but has significant adverse effects. Because it suppresses the immune system, it leaves patients more susceptible to infections. It is usually taken orally but can be delivered by intramuscular injection or intravenous injection. It has a mainly glucocorticoid effect. Prednisone is a prodrug that is converted by the liver into prednisolone, which is the active drug and also a steroid.

Medical uses

Prednisone is used for many different indications including: asthma, COPD, rheumatic disorders, allergic disorders, ulcerative colitis andCrohns disease, adrenocortical insufficiency, hypercalcemia due to cancer, thyroiditis, severe tuberculosis, lipid pneumonitis, multiple sclerosis, nephrotic syndrome, myasthenia gravis, and as part of a drug regimen to prevent rejection post organ transplant.[1] Prednisone has also been used in the treatment of migraine headaches and cluster headaches and for severe aphthous ulcer. Prednisone is used as an antitumor drug.[2] Prednisone is important in the treatment of acute lymphoblastic leukemia, Non-Hodgkin lymphomas, Hodgkin's lymphoma, multiple myeloma and other hormone-sensitive tumors, in combination with other anticancer drugs. Prednisone is also used for the treatment of the Herxheimer reaction, which is common during the treatment of syphilis, and to delay the onset of symptoms of Duchenne muscular dystrophy. The mechanism for the delay of symptoms is unknown. Because it suppresses theadrenals, it is also sometimes used in the treatment of congenital adrenal hyperplasia. Prednisone is also used to treat sarcoidosis and lupus.

Side-effects

Micrograph of fatty liver, as may be seen due to long-term prednisone use. Trichrome stain. Short-term side-effects, as with all glucocorticoids, include high blood glucose levels, especially in patients with diabetes mellitus or on other medications that increase blood glucose (such as tacrolimus) and mineralocorticoid effects such as fluid retention (it is worth noting, however, that the mineralocorticoid effects of prednisone are very minor; this is why it is not used in the management of adrenal insufficiency, unless a more potent mineralocorticoid is administered concomitantly). Additional short-term side-effects can include insomnia, euphoria and, rarely, mania (in particular, in those suffering from Bipolar disorders I and II). Long-term side-effects include Cushing's syndrome, truncal weight gain, osteoporosis, glaucoma and cataracts, type II diabetes mellitus, anddepression upon dose reduction or cessation.

Methotrexate (abbreviated MTX and formerly known as amethopterin, is

an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions.
[1]

It acts by inhibiting the metabolism of folic acid.

Methotrexate began to replace the more toxic antifolate aminopterin starting in the 1950s. The drug was developed by Yellapragada Subbarao.

Medical uses
Autoimmune disorders
It is used as a treatment for some autoimmune diseases including: rheumatoid arthritis, psoriasis, psoriatic arthritis, and Crohn's disease, to name a few. Although methotrexate was originally designed as a chemotherapy drug (in high doses), in low-doses methotrexate is a safe and well tolerated drug in the treatment of certain autoimmune diseases. Because of its efficacy and safety, lowdose methotrexate is now first-line therapy for the treatment of rheumatoid arthritis.
[2][3]

Indeed, multiple

studies and reviews showed that patients receiving methotrexate for up to 1 year had less pain, functioned better, had fewer swollen and tender joints, and had less disease activity overall as reported by themselves and their doctors. X-rays also showed that the progress of the disease slowed or stopped in many patients receiving methotrexate.
[4]

It has also been used for multiple sclerosis but is not approved by the Food and Drug Administration.

[1]

Azathioprine (/zaprin/) is a purine analogue immunosuppressive drug. It is used to

prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease(such as Crohn's disease and ulcerative Colitis), multiple sclerosis, autoimmune hepatitis, atopic dermatitis, Myasthenia Gravis,Neuromyelitis optica / NMO / Devic, restrictive lung disease, and others.

Azathioprine 50mg oral tablet Azathioprine is produced by a number of generic manufacturers and as branded names (Azasanby Salix in the U.S., Imuran by GlaxoSmithKline in Canada,the U.S., Australia, Ireland and Great Britain, Azamun in Finland and Imurel in Scandinavia and France).

History
Azathioprine was first introduced into clinical practice by Sir Roy Calne, the British pioneer in transplantation. Following the work done by SirPeter Medawar in discovering the immunological basis of rejection of transplanted tissues and organs, Calne introduced 6-mercaptopurine as an experimental immunosuppressant for kidney transplants and cardiac transplantation. When Azathioprine was discovered, he then introduced it as a less toxic replacement for 6-mercaptopurine. For many years, dual therapy with Azathioprine and steroids was the standard anti-rejection regime, until cyclosporine was introduced into clinical practice (also by Calne) in 1978.

Mechanism of action
Azathioprine is a pro-drug. Following oral ingestion, it is metabolized into the active 6-mercaptopurine, itself a purine synthesis inhibitor. 6-Mercaptopurine impedes DNA synthesis and thus inhibits the proliferation of cells, especially the fast-growing lymphocytes. T-cells and B-cells are particularly affected by the inhibition of purine synthesis. Azathioprine is an effective drug used alone in certain autoimmune diseases, or in combination with other immunosuppressants in organ transplantation. Azathrioprine blocks the downstream affects of CD28 costimulation. 6-MP (the active metabolite) interacts directly with GTP-binding protein Rac1, thus blocking upregulation of BCL-xl mRNA and protein. In vivo data indicates that inflammatory bowel disease patients treated with azathiprine have more apoptotic

mononuclear cells than untreated controls, indicating that this mechanism may be responsible for the in vivo response to the drug in this disease