may either bind twice to one strand of dna (intrastrand crosslink) or may bind once to both strands (interstrand crosslink). if the cell tries to replicate crosslinked dna during cell division, or tries to repair it, the dna strands can break. this leads to a form of programmed cell death called apoptosis. alkylating agents will work at any point in the cell cycle and thus are known as cell cycle-independent drugs. 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 subtypes of alkylating agents are the nitrogen mustards, nitrosoureas, tetrazines, aziridines, cisplatins and derivatives, and non-classical alkylating agents. nitrogen mustards include mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide and busulfan. nitrosoureas include n-nitroso-n-methylurea (mnu), carmustine (bcnu), lomustine (ccnu) and semustine (meccnu), fotemustine and streptozotocin. tetrazines include dacarbazine, mitozolomide and temozolomide. aziridines include thiotepa, mytomycin and diaziquone (azq). cisplatin and derivatives include cisplatin, carboplatin and oxaliplatin. they impair cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules. non-classical alkylating agents include procarbazine and hexamethylmelamine. antimetabolites deoxycytidine (left) and two anti-metabolite drugs (center and right), gemcitabine and decitabine. the drugs are very similar but they have subtle differences in their chemical structure. main article: antimetabolite anti-metabolites are a group of molecules that impede dna and rna synthesis. many of them have a similar structure to the building blocks of dna and rna. the building blocks are nucleotides; a molecule comprising a nucleobase, a sugar and a phosphate group. the nucleobases are divided into purines (guanine and adenine) and pyrimidines (cytosine, thymine and uracil). anti-metabolites resemble either nucleobases or nucleosides (a nucleotide without the phosphate group), but have altered chemical groups. these drugs exert their effect by either blocking the enzymes required for dna synthesis or becoming incorporated into dna or rna. by inhibiting the enzymes involved in dna synthesis, they prevent mitosis because the dna cannot duplicate itself. 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-folates, fluoropyrimidines, deoxynucleoside analogues and thiopurines. the anti-folates include methotrexate and pemetrexed. methotrexate inhibits dihydrofolate reductase (dhfr), an 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.: 55–59 : 11 pemetrexed is another anti-metabolite that affects purine and pyrimidine production, and therefore also inhibits dna synthesis. it primarily inhibits the enzyme thymidylate synthase, but also has effects on dhfr, aminoimidazole carboxamide ribonucleotide formyltransferase and glycinamide ribonucleotide formyltransferase. the fluoropyrimidines include fluorouracil and capecitabine. 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). fump becomes incorporated into rna and fdump inhibits the enzyme thymidylate synthase; both of which lead to cell death.: 11 capecitabine is a prodrug of 5-fluorouracil that is broken down in cells to produce the active drug. the deoxynucleoside analogues include cytarabine, gemcitabine, decitabine, azacitidine, fludarabine, nelarabine, cladribine, clofarabine, and pentostatin. the thiopurines include thioguanine and mercaptopurine. anti-microtubule agents vinca alkaloids prevent the assembly of microtubules, whereas taxanes prevent their disassembly. both mechanisms cause defective mitosis. anti-microtubule agents are plant-derived chemicals that block cell division by preventing microtubule function. microtubules are an important cellular structure composed of two proteins, α-tubulin and β-tubulin. they are hollow, rod-shaped structures that are required for cell division, among other cellular functions. microtubules are dynamic structures, which means that they are permanently in a state of assembly and disassembly. 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: vinca alkaloids prevent the assembly of microtubules, whereas taxanes prevent their disassembly. by doing so, they can induce mitotic catastrophe in the cancer cells. following this, cell cycle arrest occurs, which induces programmed cell death (apoptosis). these drugs can also affect blood vessel growth, an essential process that tumours utilise in order to grow and metastasise. vinca alkaloids are derived from the madagascar periwinkle, catharanthus roseus, formerly known as vinca rosea. 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. following the success of these drugs, semi-synthetic vinca alkaloids were produced: vinorelbine (used in the treatment of non-small-cell lung cancer), vindesine, and vinflunine. these drugs are cell cycle-specific. they bind to the tubulin molecules in s-phase and prevent proper microtubule formation required for m-phase. taxanes are natural and semi-synthetic drugs. the first drug of their class, paclitaxel, was originally extracted from taxus brevifolia, the pacific yew. now this drug and another in this class, docetaxel, are produced semi-synthetically from a chemical found in the bark of another yew tree, taxus baccata. podophyllotoxin is an antineoplastic lignan obtained primarily from the american mayapple (podophyllum peltatum) and himalayan mayapple (sinopodophyllum hexandrum). 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: etoposide and teniposide. topoisomerase inhibitors topoisomerase i and ii inhibitors main article: topoisomerase inhibitor topoisomerase inhibitors are drugs that affect the activity of two enzymes: topoisomerase i and topoisomerase ii. when the dna double-strand helix is unwound, during dna replication or transcription, for example, the adjacent unopened dna winds tighter (supercoils), like opening the middle of a twisted rope. the stress caused by this effect is in part aided by the topoisomerase enzymes. they produce single- or double-strand breaks into dna, reducing the tension in the dna strand. 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. two topoisomerase i inhibitors, irinotecan and topotecan, are semi-synthetically derived from camptothecin, which is obtained from the chinese ornamental tree camptotheca acuminata. drugs that target topoisomerase ii can be divided into two groups. the topoisomerase ii poisons cause increased levels enzymes bound to dna. this prevents dna replication and transcription, causes dna strand breaks, and leads to programmed cell death (apoptosis). these agents include etoposide, doxorubicin, mitoxantrone and teniposide. the second group, catalytic inhibitors, are drugs that block the activity of topoisomerase ii, and therefore prevent dna synthesis and translation because the dna cannot unwind properly. this group includes novobiocin, merbarone, and aclarubicin, which also have other significant mechanisms of action. cytotoxic antibiotics the cytotoxic antibiotics are a varied group of drugs that have various mechanisms of action. the common theme that they share in their chemotherapy indication is that they interrupt cell division. the most important subgroup is the anthracyclines and the bleomycins; other prominent examples include mitomycin c and actinomycin. among the anthracyclines, doxorubicin and daunorubicin were the first, and were obtained from the bacterium streptomyces peucetius. derivatives of these compounds include epirubicin and idarubicin. other clinically used drugs in the anthracycline group are pirarubicin, aclarubicin, and mitoxantrone. the mechanisms of anthracyclines include dna intercalation (molecules insert between the two strands of dna), generation of highly reactive free radicals that damage intercellular molecules and topoisomerase inhibition. actinomycin is a complex molecule that intercalates dna and prevents rna synthesis. bleomycin, a glycopeptide isolated from streptomyces verticillus, also intercalates dna, but produces free radicals that damage dna. this occurs when bleomycin binds to a metal ion, becomes chemically reduced and reacts with oxygen.: 87 mitomycin is a cytotoxic antibiotic with the ability to alkylate dna. delivery two girls with acute lymphoblastic leukemia receiving chemotherapy. the girl on the left has a central venous catheter inserted in her neck. the girl on the right has a peripheral venous catheter. the arm board stabilizes the arm during needle insertion. anti-cancer iv drip is seen at top right. most chemotherapy is delivered intravenously, although a number of agents can be administered orally (e.g., melphalan, busulfan, capecitabine). according to a recent (2016) systematic review, oral therapies present additional challenges for patients and care teams to maintain and support adherence to treatment plans. there are many intravenous methods of drug delivery, known as vascular access devices. these include the winged infusion device, peripheral venous catheter, midline catheter, peripherally inserted central catheter (picc), central venous catheter and implantable port. the devices have different applications regarding duration of chemotherapy treatment, method of delivery and types of chemotherapeutic agent.: 94–95 depending on the person, the cancer, the stage of cancer, the type of chemotherapy, and the dosage, intravenous chemotherapy may be given on either an inpatient or an outpatient basis. for continuous, frequent or prolonged intravenous chemotherapy administration, various systems may be surgically inserted into the vasculature to maintain access.: 113–118 commonly used systems are the hickman line, the port-a-cath, and the picc line. these have a lower infection risk, are much less prone to phlebitis or extravasation, and eliminate the need for repeated insertion of peripheral cannulae. isolated limb perfusion (often used in melanoma), or isolated infusion of chemotherapy into the liver or the lung have been used to treat some tumors. the main purpose of these approaches is to deliver a very high dose of chemotherapy to tumor sites without causing overwhelming systemic damage. these approaches can help control solitary or limited metastases, but they are by definition not systemic, and, therefore, do not treat distributed metastases or micrometastases. topical chemotherapies, such as 5-fluorouracil, are used to treat some cases of non-melanoma skin cancer. if the cancer has central nervous system involvement, or with meningeal disease, intrathecal chemotherapy may be administered. adverse effects chemotherapeutic techniques have a range of side effects that depend on the type of medications used. the most common medications affect mainly the fast-dividing cells of the body, such as blood cells and the cells lining the mouth, stomach, and intestines. chemotherapy-related toxicities can occur acutely after administration, within hours or days, or chronically, from weeks to years.: 265 immunosuppression and myelosuppression virtually all chemotherapeutic regimens can cause depression of the immune system, often by paralysing the bone marrow and leading to a decrease of white blood cells, red blood cells, and platelets. anemia and thrombocytopenia may require blood transfusion. neutropenia (a decrease of the neutrophil granulocyte count below 0.5 x 109/litre) can be improved with synthetic g-csf (granulocyte-colony-stimulating factor, e.g., filgrastim, lenograstim). in very severe myelosuppression, which occurs in some regimens, almost all the bone marrow stem cells (cells that produce white and red blood cells) are destroyed, meaning allogenic or autologous bone marrow cell transplants are necessary. (in autologous bmts, cells are removed from the person before the treatment, multiplied and then re-injected afterward; in allogenic bmts, the source is a donor.) however, some people still develop diseases because of this interference with bone marrow. although people receiving chemotherapy are encouraged to wash their hands, avoid sick people, and take other infection-reducing steps, about 85% of infections are due to naturally occurring microorganisms in the person's own gastrointestinal tract (including oral cavity) and skin.: 130 this may manifest as systemic infections, such as sepsis, or as localized outbreaks, such as herpes simplex, shingles, or other members of the herpesviridea. the risk of illness and death can be reduced by taking common antibiotics such as quinolones or trimethoprim/sulfamethoxazole before any fever or sign of infection appears. quinolones show effective prophylaxis mainly with hematological cancer. however, in general, for every five people who are immunosuppressed following chemotherapy who take an antibiotic, one fever can be prevented; for every 34 who take an antibiotic, one death can be prevented. sometimes, chemotherapy treatments are postponed because the immune system is suppressed to a critically low level. in japan, the government has approved the use of some medicinal mushrooms like trametes versicolor, to counteract depression of the immune system in people undergoing chemotherapy. trilaciclib