cure their cancer. the blood–brain barrier poses an obstacle to delivery of chemotherapy to the brain. this is because the brain has an extensive system in place to protect it from harmful chemicals. drug transporters can pump out drugs from the brain and brain's blood vessel cells into the cerebrospinal fluid and blood circulation. these transporters pump out most chemotherapy drugs, which reduces their efficacy for treatment of brain tumors. only small lipophilic alkylating agents such as lomustine or temozolomide are able to cross this blood–brain barrier. blood vessels in tumors are very different from those seen in normal tissues. as a tumor grows, tumor cells furthest away from the blood vessels become low in oxygen (hypoxic). to counteract this they then signal for new blood vessels to grow. the newly formed tumor vasculature is poorly formed and does not deliver an adequate blood supply to all areas of the tumor. this leads to issues with drug delivery because many drugs will be delivered to the tumor by the circulatory system. resistance resistance is a major cause of treatment failure in chemotherapeutic drugs. there are a few possible causes of resistance in cancer, one of which is the presence of small pumps on the surface of cancer cells that actively move chemotherapy from inside the cell to the outside. cancer cells produce high amounts of these pumps, known as p-glycoprotein, in order to protect themselves from chemotherapeutics. research on p-glycoprotein and other such chemotherapy efflux pumps is currently ongoing. medications to inhibit the function of p-glycoprotein are undergoing investigation, but due to toxicities and interactions with anti-cancer drugs their development has been difficult. another mechanism of resistance is gene amplification, a process in which multiple copies of a gene are produced by cancer cells. this overcomes the effect of drugs that reduce the expression of genes involved in replication. with more copies of the gene, the drug can not prevent all expression of the gene and therefore the cell can restore its proliferative ability. cancer cells can also cause defects in the cellular pathways of apoptosis (programmed cell death). as most chemotherapy drugs kill cancer cells in this manner, defective apoptosis allows survival of these cells, making them resistant. many chemotherapy drugs also cause dna damage, which can be repaired by enzymes in the cell that carry out dna repair. upregulation of these genes can overcome the dna damage and prevent the induction of apoptosis. mutations in genes that produce drug target proteins, such as tubulin, can occur which prevent the drugs from binding to the protein, leading to resistance to these types of drugs. drugs used in chemotherapy can induce cell stress, which can kill a cancer cell; however, under certain conditions, cells stress can induce changes in gene expression that enables resistance to several types of drugs. in lung cancer, the transcription factor nfκb is thought to play a role in resistance to chemotherapy, via inflammatory pathways. cytotoxics and targeted therapies targeted therapies are a relatively new class of cancer drugs that can overcome many of the issues seen with the use of cytotoxics. they are divided into two groups: small molecule and antibodies. the massive toxicity seen with the use of cytotoxics is due to the lack of cell specificity of the drugs. they will kill any rapidly dividing cell, tumor or normal. targeted therapies are designed to affect cellular proteins or processes that are utilised by the cancer cells. this allows a high dose to cancer tissues with a relatively low dose to other tissues. although the side effects are often less severe than that seen of cytotoxic chemotherapeutics, life-threatening effects can occur. initially, the targeted therapeutics were supposed to be solely selective for one protein. now it is clear that there is often a range of protein targets that the drug can bind. an example target for targeted therapy is the bcr-abl1 protein produced from the philadelphia chromosome, a genetic lesion found commonly in chronic myelogenous leukemia and in some patients with acute lymphoblastic leukemia. this fusion protein has enzyme activity that can be inhibited by imatinib, a small molecule drug. mechanism of action the four phases of the cell cycle. g1 – the initial growth phase. s – the phase in which dna is synthesised. g2 – the second growth phase in preparation for cell division. m – mitosis; where the cell divides to produce two daughter cells that continue the cell cycle. cancer is the uncontrolled growth of cells coupled with malignant behaviour: invasion and metastasis (among other features). it is caused by the interaction between genetic susceptibility and environmental factors. these factors lead to accumulations of genetic mutations in oncogenes (genes that control the growth rate of cells) and tumor suppressor genes (genes that help to prevent cancer), which gives cancer cells their malignant characteristics, such as uncontrolled growth.: 93–94 in the broad sense, most chemotherapeutic drugs work by impairing mitosis (cell division), effectively targeting fast-dividing cells. as these drugs cause damage to cells, they are termed cytotoxic. they prevent mitosis by various mechanisms including damaging dna and inhibition of the cellular machinery involved in cell division. one theory as to why these drugs kill cancer cells is that they induce a programmed form of cell death known as apoptosis. as chemotherapy affects cell division, tumors with high growth rates (such as acute myelogenous leukemia and the aggressive lymphomas, including hodgkin's disease) are more sensitive to chemotherapy, as a larger proportion of the targeted cells are undergoing cell division at any time. malignancies with slower growth rates, such as indolent lymphomas, tend to respond to chemotherapy much more modestly. heterogeneic tumours may also display varying sensitivities to chemotherapy agents, depending on the subclonal populations within the tumor. cells from the immune system also make crucial contributions to the antitumor effects of chemotherapy. for example, the chemotherapeutic drugs oxaliplatin and cyclophosphamide can cause tumor cells to die in a way that is detectable by the immune system (called immunogenic cell death), which mobilizes immune cells with antitumor functions. chemotherapeutic drugs that cause cancer immunogenic tumor cell death can make unresponsive tumors sensitive to immune checkpoint therapy. other uses some chemotherapy drugs are used in diseases other than cancer, such as in autoimmune disorders, and noncancerous plasma cell dyscrasia. in some cases they are often used at lower doses, which means that the side effects are minimized, while in other cases doses similar to ones used to treat cancer are used. methotrexate is used in the treatment of rheumatoid arthritis (ra), psoriasis, ankylosing spondylitis and multiple sclerosis. the anti-inflammatory response seen in ra is thought to be due to increases in adenosine, which causes immunosuppression; effects on immuno-regulatory cyclooxygenase-2 enzyme pathways; reduction in pro-inflammatory cytokines; and anti-proliferative properties. although methotrexate is used to treat both multiple sclerosis and ankylosing spondylitis, its efficacy in these diseases is still uncertain. cyclophosphamide is sometimes used to treat lupus nephritis, a common symptom of systemic lupus erythematosus. dexamethasone along with either bortezomib or melphalan is commonly used as a treatment for al amyloidosis. recently, bortezomid in combination with cyclophosphamide and dexamethasone has also shown promise as a treatment for al amyloidosis. other drugs used to treat myeloma such as lenalidomide have shown promise in treating al amyloidosis. chemotherapy drugs are also used in conditioning regimens prior to bone marrow transplant (hematopoietic stem cell transplant). conditioning regimens are used to suppress the recipient's immune system in order to allow a transplant to engraft. cyclophosphamide is a common cytotoxic drug used in this manner and is often used in conjunction with total body irradiation. chemotherapeutic drugs may be used at high doses to permanently remove the recipient's bone marrow cells (myeloablative conditioning) or at lower doses that will prevent permanent bone marrow loss (non-myeloablative and reduced intensity conditioning). when used in non-cancer setting, the treatment is still called "chemotherapy", and is often done in the same treatment centers used for people with cancer. occupational exposure and safe handling in the 1970s, antineoplastic (chemotherapy) drugs were identified as hazardous, and the american society of health-system pharmacists (ashp) has since then introduced the concept of hazardous drugs after publishing a recommendation in 1983 regarding handling hazardous drugs. the adaptation of federal regulations came when the u.s. occupational safety and health administration (osha) first released its guidelines in 1986 and then updated them in 1996, 1999, and, most recently, 2006. the national institute for occupational safety and health (niosh) has been conducting an assessment in the workplace since then regarding these drugs. occupational exposure to antineoplastic drugs has been linked to multiple health effects, including infertility and possible carcinogenic effects. a few cases have been reported by the niosh alert report, such as one in which a female pharmacist was diagnosed with papillary transitional cell carcinoma. twelve years before the pharmacist was diagnosed with the condition, she had worked for 20 months in a hospital where she was responsible for preparing multiple antineoplastic drugs. the pharmacist didn't have any other risk factor for cancer, and therefore, her cancer was attributed to the exposure to the antineoplastic drugs, although a cause-and-effect relationship has not been established in the literature. another case happened when a malfunction in biosafety cabinetry is believed to have exposed nursing personnel to antineoplastic drugs. investigations revealed evidence of genotoxic biomarkers two and nine months after that exposure. routes of exposure antineoplastic drugs are usually given through intravenous, intramuscular, intrathecal, or subcutaneous administration. in most cases, before the medication is administered to the patient, it needs to be prepared and handled by several workers. any worker who is involved in handling, preparing, or administering the drugs, or with cleaning objects that have come into contact with antineoplastic drugs, is potentially exposed to hazardous drugs. health care workers are exposed to drugs in different circumstances, such as when pharmacists and pharmacy technicians prepare and handle antineoplastic drugs and when nurses and physicians administer the drugs to patients. additionally, those who are responsible for disposing antineoplastic drugs in health care facilities are also at risk of exposure. dermal exposure is thought to be the main route of exposure due to the fact that significant amounts of the antineoplastic agents have been found in the gloves worn by healthcare workers who prepare, handle, and administer the agents. another noteworthy route of exposure is inhalation of the drugs' vapors. multiple studies have investigated inhalation as a route of exposure, and although air sampling has not shown any dangerous levels, it is still a potential route of exposure. ingestion by hand to mouth is a route of exposure that is less likely compared to others because of the enforced hygienic standard in the health institutions. however, it is still a potential route, especially in the workplace, outside of a health institute. one can also be exposed to these hazardous drugs through injection by needle sticks. research conducted in this area has established that occupational exposure occurs by examining evidence in multiple urine samples from health care workers. hazards hazardous drugs expose health care workers to serious health risks. many studies show that antineoplastic drugs could have many side effects on the reproductive system, such as fetal loss, congenital malformation, and infertility. health care workers who are exposed to antineoplastic drugs on many occasions have adverse reproductive outcomes such as spontaneous abortions, stillbirths, and congenital malformations. moreover, studies have shown that exposure to these drugs leads to menstrual cycle irregularities. antineoplastic drugs may also increase the risk of learning disabilities among children of health care workers who are exposed to these hazardous substances. moreover, these drugs have carcinogenic effects. in the past five decades, multiple studies have shown the carcinogenic effects of exposure to antineoplastic drugs. similarly, there have been research studies that linked alkylating agents with humans developing leukemias. studies have reported elevated risk of breast cancer, nonmelanoma skin cancer, and cancer of the rectum among nurses who are exposed to these drugs. other investigations revealed that there is a potential genotoxic effect from anti-neoplastic drugs to workers in health care settings. safe handling in health care settings as of 2018, there were no occupational exposure limits set for antineoplastic drugs, i.e., osha or the american conference of governmental industrial hygienists (acgih) have not set workplace safety guidelines. preparation niosh recommends using a ventilated