Nitrogen mustard - Wikipedia
Chemotherapy was first developed at the beginning of the 20th century, although it was not Nitrogen mustard and other derivatives of mustard gas are called alkylating agent due to their ability to dubaiairporthotel.info Study assesses link between Vitamin D intake and obesity in occupational asthma patients. Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, Cyclophosphamide is in the alkylating agent and nitrogen mustard family of medications. Chemotherapy drugs can be divided into several groups based on factors such as how they work, their chemical structure, and their relationship to another drug.
The BSA is usually calculated with a mathematical formula or a nomogramusing the recipient's weight and height, rather than by direct measurement of body area. This formula was originally derived in a study and attempted to translate medicinal doses established with laboratory animals to equivalent doses for humans. The reason for this is that the formula only takes into account the individual's weight and height. Drug absorption and clearance are influenced by multiple factors, including age, gender, metabolism, disease state, organ function, drug-to-drug interactions, genetics, and obesity, which has a major impact on the actual concentration of the drug in the person's bloodstream.
Some people are overdosed while others are underdosed. Similar results were found in a study involving people with colorectal cancer who were treated with the popular FOLFOX regimen.
Median progression free survival PFS and overall survival OS both improved by six months in the dose adjusted group. With an established target exposure for optimized treatment effectiveness with minimized toxicities, dosing can be personalized to achieve target exposure and optimal results for each person. Such an algorithm was used in the clinical trials cited above and resulted in significantly improved treatment outcomes. Oncologists are already individualizing dosing of some cancer drugs based on exposure.
Simple blood tests are also available for dose optimization of methotrexate 5-FU, paclitaxeland docetaxel. This has the effect of sparing the drug from degradation or elimination by the hepatic monocyte macrophages, resulting in a greater accumulation of the drug in the tumor. Types[ edit ] Two DNA bases that are cross-linked by a nitrogen mustard. Different nitrogen mustards will have different chemical groups R.
The nitrogen mustards most commonly alkylate the N7 nitrogen of guanine as shown here but other atoms can be alkylated. Alkylating antineoplastic agent Alkylating agents are the oldest group of chemotherapeutics in use today. Originally derived from mustard gas used in World War Ithere are now many types of alkylating agents in use.
This ability to bind covalently to DNA via their alkyl group is the primary cause for their anti-cancer effects. If the cell tries to replicate crosslinked DNA during cell divisionor tries to repair it, the DNA strands can break.
Evolution of Cancer Treatments: Chemotherapy
This leads to a form of programmed cell death called apoptosis. For this reason the effect on the cell is dose dependent; the fraction of cells that die is directly proportional to the dose of drug. The drugs are very similar but they have subtle differences in their chemical structure.
The building blocks are nucleotides ; a molecule comprising a nucleobasea sugar and a phosphate group. The nucleobases are divided into purines guanine and adenine and pyrimidines cytosinethymine and uracil. Anti-metabolites resemble either nucleobases or nucleosides a nucleotide without the phosphate groupbut have altered chemical groups. Also, after misincorporation of the molecules into DNA, DNA damage can occur and programmed cell death apoptosis is induced.
Unlike alkylating agents, anti-metabolites are cell cycle dependent. This means that they only work during a specific part of the cell cycle, in this case S-phase the DNA synthesis phase. For this reason, at a certain dose, the effect plateaus and proportionally no more cell death occurs with increased doses.
Subtypes of the anti-metabolites are the anti-folatesfluoropyrimidines, deoxynucleoside analogues and thiopurines.
Methotrexate inhibits dihydrofolate reductase DHFRan enzyme that regenerates tetrahydrofolate from dihydrofolate. When the enzyme is inhibited by methotrexate, the cellular levels of folate coenzymes diminish.
These are required for thymidylate and purine production, which are both essential for DNA synthesis and cell division. It primarily inhibits the enzyme thymidylate synthasebut also has effects on DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase and glycinamide ribonucleotide formyltransferase.
Fluorouracil is a nucleobase analogue that is metabolised in cells to form at least two active products; 5-fluourouridine monophosphate FUMP and 5-fluoro-2'-deoxyuridine 5'-phosphate fdUMP.
The thiopurines include thioguanine and mercaptopurine. Both mechanisms cause defective mitosis. Anti-microtubule agents are plant -derived chemicals that block cell division by preventing microtubule function. They are hollow rod shaped structures that are required for cell division, among other cellular functions.
Mustard gas blisters skin and lungs causing disfigurement and death. As a weapon, Nitrogen Mustard is code named HN2. Transformation from weapon to drug also involved government sponsored research.
Stewart Alexander first observed myelo-suppression from mustard gas, in people exposed to it after a German air raid. After the war, the Dean of the Yale Medical School won a secret government contract to study chemical warfare. He chose two assistant professors for this task—Goodman and Gilman, yes, the ones who later wrote your the textbook of pharmacology. They worked out an antidote thiosulate but more importantly made a more stable chemical by substituting nitrogen for sulfur.
They persuaded a a chest surgeon to provide the first patient ever to be treated with IV chemotherapy. A 47 year old Polish immigrant working at a ball-bearing factory in Connecticut had lymphosarcoma. The second and third met with resistance and he died after three months in the hospital.
Both classes of drug were isolated and characterized by the laboratory of Monroe Wall at the Research Triangle Institute. Taxanes[ edit ] Paclitaxel Taxol was a novel antimitotic agent that promoted microtubule assembly. This agent proved difficult to synthesize and could only be obtained from the bark of the Pacific Yew treewhich forced the NCI into the costly business of harvesting substantial quantities of yew trees from public lands.
After 4 years of clinical testing in solid tumours, it was found in 23 years after its initial discovery to be effective in ovarian cancer therapy. Notably, this agent, although developed by the NCI in partnership with Bristol-Myers Squibbwas exclusively marketed by BMS who had utilized the synthetic methodology developed by Robert Holton at Florida State University who went on to make over a billion dollars profit from Taxol.
Chemotherapy's War Legacy | SERMO
Camptothecinderived from a Chinese ornamental tree, inhibits topoisomerase I, an enzyme that allows DNA unwinding. Despite showing promise in preclinical studies, the agent had little antitumour activity in early clinical trials, and dosing was limited by kidney toxicity: In a more stable analogue, irinotecanwon Food and Drug Administration FDA approval for the treatment of colon cancer. Later, this agent would also be used to treat lung and ovarian cancers.
Platinum-based agents[ edit ] Cisplatina platinum -based compound, was discovered by a Michigan State University researcher, Barnett Rosenbergworking under an NCI contract.
This was yet another serendipitous discovery: Rosenberg had initially wanted to explore the possible effects of an electric field on the growth of bacteria.Tear Gas, Mustard Gas, Phosgene... "Protection Against Chemical Warfare" ~ 1942 US Navy
He observed that the bacteria unexpectedly ceased to divide when placed in an electric field. Excited, he spent months of testing to try to explain this phenomenon. He was disappointed to find that the cause was an experimental artifact — the inhibition of bacterial division was pinpointed to an electrolysis product of the platinum electrode rather than the electrical field.
This accidental discovery, however, soon initiated a series of investigations and studies into the effects of platinum compounds on cell division, culminating in the synthesis of cisplatin. This drug was pivotal in the cure of testicular cancer. Subsequently, Eve Wiltshaw and others at the Institute of Cancer Research in the United Kingdom extended the clinical usefulness of the platinum compounds with their development of carboplatina cisplatin derivative with broad antitumour activity and comparatively less nephrotoxicity.
Fludarabine phosphate, a purine analogue which has become a mainstay in treatment of patients with chronic lymphocytic leukaemia, was another similar development by Montgomery. Anthracyclines and epipodophyllotoxins[ edit ] Other effective molecules also came from industry during the period of toincluding anthracyclines  and epipodophyllotoxins — both of which inhibited the action of topoisomerase IIan enzyme crucial for DNA synthesis.
Supportive care during chemotherapy[ edit ] As is obvious from their origins, the above cancer chemotherapies are essentially poisons. Patients receiving these agents experienced severe side-effects that limited the doses which could be administered, and hence limited the beneficial effects. Clinical investigators realized that the ability to manage these toxicities was crucial to the success of cancer chemotherapy. Several examples are noteworthy.
Many chemotherapeutic agents cause profound suppression of the bone marrow. This is reversible, but takes time to recover. Support with platelet and red-cell transfusions as well as broad-spectrum antibiotics in case of infection during this period is crucial to allow the patient to recover. Several practical factors are also worth mentioning.
Most of these agents caused very severe nausea termed chemotherapy-induced nausea and vomiting CINV in the literature which, while not directly causing patient deaths, was unbearable at higher doses.
History of cancer chemotherapy - Wikipedia
The development of new drugs to prevent nausea the prototype of which was ondansetron was of great practical use, as was the design of indwelling intravenous catheters e. Hickman lines and PICC lines which allowed safe administration of chemotherapy as well as supportive therapy. Bone marrow transplantation[ edit ] One important contribution during this period[ when?
The patient's bone marrow was first harvested, the chemotherapy administered, and the harvested marrow then returned to patient a few days later. This approach, termed autologous bone marrow transplantationwas initially thought to be of benefit to a wide group of patients, including those with advanced breast cancer.
However, rigorous studies have failed to confirm this benefit, and autologous transplantation is no longer widely used for solid tumors. The proven curative benefits of high doses of chemotherapy afforded by autologous bone marrow rescue are limited to both Hodgkin's and selected non-Hodgkin's lymphoma patients who have failed therapy with conventional combination chemotherapy.