Alkylating antineoplastic agent - Wikipedia
An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches 6 Limitations; 7 See also; 8 References; 9 External links Because of secrecy surrounding the war gas program, these results were not published in Bari, Italy, where survivors exposed to mustard gas became leukopenic. Sulfur mustard, commonly known as mustard gas, is the prototypical substance of the Development of the first chemotherapy drug; Disposal. Detection in biological fluids. 7 See also; 8 References; 9 External links. The era of cancer chemotherapy began in the s with the first use of nitrogen mustards and Goodman and Gilman observed that mustard gas was too volatile an agent to be suitable for laboratory experiments. . at the Southern Research Institute, synthesized nitrosoureas, an alkylating agent which cross- links DNA.
If the cell tries to replicate crosslinked DNA during cell divisionor tries to repair it, the DNA strands can break. 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.
Alkylating antineoplastic agent
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. Vinca alkaloids and taxanes are the two main groups of anti-microtubule agents, and although both of these groups of drugs cause microtubule dysfunction, their mechanisms of action are completely opposite.
The vinca alkaloids prevent the formation of the microtubules, whereas the taxanes prevent the microtubule disassembly.
Sulfur mustard - Wikipedia
By doing so, they prevent the cancer cells from completing mitosis. Following this, cell cycle arrest occurs, which induces programmed cell death apoptosis. They bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules.
The original vinca alkaloids are natural products that include vincristine and vinblastine. They bind to the tubulin molecules in S-phase and prevent proper microtubule formation required for M-phase. The first drug of their class, paclitaxelwas originally extracted from the Pacific Yew tree, Taxus brevifolia. Now this drug and another in this class, docetaxelare produced semi-synthetically from a chemical found in the bark of another Yew tree; Taxus baccata.
These drugs promote microtubule stability, preventing their disassembly. Paclitaxel prevents the cell cycle at the boundary of G2-M, whereas docetaxel exerts its effect during S-phase. Taxanes present difficulties in formulation as medicines because they are poorly soluble in water. It has anti-microtubule activity, and its mechanism is similar to that of vinca alkaloids in that they bind to tubulin, inhibiting microtubule formation.
Podophyllotoxin is used to produce two other drugs with different mechanisms of action: When the DNA double-strand helix is unwound, during DNA replication or transcriptionfor example, the adjacent unopened DNA winds tighter supercoilslike opening the middle of a twisted rope. The stress caused by this effect is in part aided by the topoisomerase enzymes.
This allows the normal unwinding of DNA to occur during replication or transcription. Inhibition of topoisomerase I or II interferes with both of these processes. Agents requiring activation[ edit ] Some of the substances require conversion into active substances in vivo e.
Cyclophosphamide is one of the most potent immunosuppressive substances. In small dosages, it is very efficient in the therapy of systemic lupus erythematosusautoimmune hemolytic anemiagranulomatosis with polyangiitisand other autoimmune diseases. High dosages cause pancytopenia and hemorrhagic cystitis. Dialkylating agents, limpet attachment, and monoalkylating agents[ edit ] Dialkylating agents can react with two different 7-N-guanine residues, and, if these are in different strands of DNA, the result is cross-linkage of the DNA strands, which prevents uncoiling of the DNA double helix.
If the two guanine residues are in the same strand, the result is called limpet attachment of the drug molecule to the DNA.
Busulfan is an example of a dialkylating agent: Methanesulfonate can be eliminated as a leaving group. Both ends of the molecule can be attacked by DNA bases, producing a butylene crosslink between two different bases. With incremental refinements of original regimens, using randomized clinical studies by St. This approach was extended to the lymphomas in by Vincent T. DeVita and George Canellos at the NCI, who ultimately proved in the late s that nitrogen mustard, vincristine, procarbazine and prednisone — known as the MOPP regimen — could cure patients with Hodgkin's and non-Hodgkin's lymphoma.
Currently, nearly all successful cancer chemotherapy regimens use this paradigm of multiple drugs given simultaneously, called combination chemotherapy or polychemotherapy.
Adjuvant therapy[ edit ] As predicted by studies in animal models, drugs were most effective when used in patients with tumours of smaller volume. Another important strategy developed from this — if the tumour burden could be reduced first by surgery, then chemotherapy may be able to clear away any remaining malignant cells, even if it would not have been potent enough to destroy the tumor in its entirety.
This approach was termed "adjuvant therapy". Emil Frei first demonstrated this effect — high doses of methotrexate prevented recurrence of osteosarcoma following surgical removal of the primary tumour. Similarly, the landmark trials of Bernard Fisherchair of the National Surgical Adjuvant Breast and Bowel Project, and of Gianni Bonadonnaworking in the Istituto Nazionale Tumori di MilanoItalyproved that adjuvant chemotherapy after complete surgical resection of breast tumours significantly extended survival — particularly in more advanced cancer.
Gordon Zubrodwho had formerly led the development of antimalarial agents for the United States Army, took over the Division of Cancer Treatment of the NCI and guided development of new drugs. In the two decades that followed the establishment of the NCCSC, a large network of cooperative clinical trial groups evolved under the auspices of the NCI to test anticancer agents.
Zubrod had a particular interest in natural products, and established a broad programme for collecting and testing plant and marine sources, a controversial programme that led to the discovery of taxanes in and camptothecins in 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.Mustard Gas’ Unbelievable Role in the War on Cancer
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.
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. 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.
Nitrogen mustard - Wikipedia
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.