Manipulation of genetic expression by modification of messenger RNA is now within our reach, and the basic concepts are suc- cinctly reviewed as a primer on future biochemical engineering of new anti- cancer molecules. Another concept that appears to be worthy of further study in both experimental and clinical chemotherapy concerns obs'ervations on the modulation of activity by the nucleoside transport inhibitor, dipyri- damole.
How potentiation of several anticancer drugs occurs has practical, as well as theoretical, ramifications, discussed by Goel and HowelL Finally, O'Dwyer and La Creta present a fresh look at sensitization of chemotherapy by the hypoxic radiosensitizer, SR Read more Read less. Product details Hardcover: pages Publisher: Springer; ed. No customer reviews. 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 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.
The Importance of Planned Dose of Chemotherapy on Time: Do We Need to Change Our Clinical Practice?
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. 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. Cancer is the uncontrolled growth of cells coupled with malignant behaviour: invasion and metastasis among other features. 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. 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. Cells from the immune system also make crucial contributions to the antitumor effects of chemotherapy. 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. 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.
In the s, 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 regarding handling hazardous drugs. The adaptation of federal regulations came when the U. Occupational Safety and Health Administration OSHA first released its guidelines in and then updated them in , , and, most recently, 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. 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. Antineoplastic drugs are usually given through intravenous , intramuscular. In most cases, before the medication is administered to the patient, it needs to be prepared and handled by several workers.
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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. 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.
As of , there were no occupational exposure limits set for antineoplastic drugs, i. NIOSH recommends using a ventilated cabinet that is designed to decrease worker exposure. Additionally, it recommends training of all staff, the use of cabinets, implementing an initial evaluation of the technique of the safety program, and wearing protective gloves and gowns when opening drug packaging, handling vials, or labeling.
When wearing personal protective equipment , one should inspect gloves for physical defects before use and always wear double gloves and protective gowns. Health care workers are also required to wash their hands with water and soap before and after working with antineoplastic drugs, change gloves every 30 minutes or whenever punctured, and discard them immediately in a chemotherapy waste container. The gowns used should be disposable gowns made of polyethylene-coated polypropylene.
When wearing gowns, individuals should make sure that the gowns are closed and have long sleeves. When preparation is done, the final product should be completely sealed in a plastic bag. The health care worker should also wipe all waste containers inside the ventilated cabinet before removing them from the cabinet. Finally, workers should remove all protective wear and put them in a bag for their disposal inside the ventilated cabinet.
Drugs should only be administered using protective medical devices such as needle lists and closed systems and techniques such as priming of IV tubing by pharmacy personnel inside a ventilated cabinet. Workers should always wear personal protective equipment such as double gloves, goggles, and protective gowns when opening the outer bag and assembling the delivery system to deliver the drug to the patient, and when disposing of all material used in the administration of the drugs. Hospital workers should never remove tubing from an IV bag that contains an antineoplastic drug, and when disconnecting the tubing in the system, they should make sure the tubing has been thoroughly flushed.
After removing the IV bag, the workers should place it together with other disposable items directly in the yellow chemotherapy waste container with the lid closed. Protective equipment should be removed and put into a disposable chemotherapy waste container. After this has been done, one should double bag the chemotherapy waste before or after removing one's inner gloves.
Moreover, one must always wash one's hands with soap and water before leaving the drug administration site. All employees whose jobs in health care facilities expose them to hazardous drugs must receive training. Training should include shipping and receiving personnel, housekeepers, pharmacists, assistants, and all individuals involved in the transportation and storage of antineoplastic drugs.
These individuals should receive information and training to inform them of the hazards of the drugs present in their areas of work. They should be informed and trained on operations and procedures in their work areas where they can encounter hazards, different methods used to detect the presence of hazardous drugs and how the hazards are released, and the physical and health hazards of the drugs, including their reproductive and carcinogenic hazard potential. Additionally, they should be informed and trained on the measures they should take to avoid and protect themselves from these hazards.
This information ought to be provided when health care workers come into contact with the drugs, that is, perform the initial assignment in a work area with hazardous drugs. Moreover, training should also be provided when new hazards emerge as well as when new drugs, procedures, or equipment are introduced. When performing cleaning and decontaminating the work area where antineoplastic drugs are used, one should make sure that there is sufficient ventilation to prevent the buildup of airborne drug concentrations.
When cleaning the work surface, hospital workers should use deactivation and cleaning agents before and after each activity as well as at the end of their shifts. Cleaning should always be done using double protective gloves and disposable gowns. After employees finish up cleaning, they should dispose of the items used in the activity in a yellow chemotherapy waste container while still wearing protective gloves.
After removing the gloves, they should thoroughly wash their hands with soap and water. Anything that comes into contact or has a trace of the antineoplastic drugs, such as needles, empty vials, syringes, gowns, and gloves, should be put in the chemotherapy waste container. A written policy needs to be in place in case of a spill of antineoplastic products.
The policy should address the possibility of various sizes of spills as well as the procedure and personal protective equipment required for each size. A trained worker should handle a large spill and always dispose of all cleanup materials in the chemical waste container according to EPA regulations, not in a yellow chemotherapy waste container.
A medical surveillance program must be established. In case of exposure, occupational health professionals need to ask for a detailed history and do a thorough physical exam. They should test the urine of the potentially exposed worker by doing a urine dipstick or microscopic examination, mainly looking for blood, as several antineoplastic drugs are known to cause bladder damage. Urinary mutagenicity is a marker of exposure to antineoplastic drugs that was first used by Falck and colleagues in and uses bacterial mutagenicity assays.
Apart from being nonspecific, the test can be influenced by extraneous factors such as dietary intake and smoking and is, therefore, used sparingly. However, the test played a significant role in changing the use of horizontal flow cabinets to vertical flow biological safety cabinets during the preparation of antineoplastic drugs because the former exposed health care workers to high levels of drugs. Biomarkers of exposure to antineoplastic drugs commonly include urinary platinum , methotrexate , urinary cyclophosphamide and ifosfamide , and urinary metabolite of 5-fluorouracil.
In addition to this, there are other drugs used to measure the drugs directly in the urine, although they are rarely used. A measurement of these drugs directly in one's urine is a sign of high exposure levels and that an uptake of the drugs is happening either through inhalation or dermally. There is an extensive list of antineoplastic agents. Several classification schemes have been used to subdivide the medicines used for cancer into several different types. The first use of small-molecule drugs to treat cancer was in the early 20th century, although the specific chemicals first used were not originally intended for that purpose.
Mustard gas was used as a chemical warfare agent during World War I and was discovered to be a potent suppressor of hematopoiesis blood production. The survivors were later found to have very low white blood cell counts. The first chemotherapy drug to be developed from this line of research was mustine. Since then, many other drugs have been developed to treat cancer, and drug development has exploded into a multibillion-dollar industry, although the principles and limitations of chemotherapy discovered by the early researchers still apply.
The word chemotherapy without a modifier usually refers to cancer treatment, but its historical meaning was broader. In today's usage , the sense "any treatment of disease with drugs" is often expressed with the word pharmacotherapy. The top 10 best-selling in terms of revenue cancer drugs of . Specially targeted delivery vehicles aim to increase effective levels of chemotherapy for tumor cells while reducing effective levels for other cells. This should result in an increased tumor kill or reduced toxicity or both.
Antibody-drug conjugates ADCs comprise an antibody , drug and a linker between them. The antibody will be targeted at a preferentially expressed protein in the tumour cells known as a tumor antigen or on cells that the tumor can utilise, such as blood vessel endothelial cells. They bind to the tumor antigen and are internalised, where the linker releases the drug into the cell.
These specially targeted delivery vehicles vary in their stability, selectivity, and choice of target, but, in essence, they all aim to increase the maximum effective dose that can be delivered to the tumor cells. The first approved drug of this type was gemtuzumab ozogamicin Mylotarg , released by Wyeth now Pfizer. The drug was approved to treat acute myeloid leukemia , but has now been withdrawn from the market because the drug did not meet efficacy targets in further clinical trials.
Nanoparticles are 1— nanometer nm sized particles that can promote tumor selectivity and aid in delivering low- solubility drugs. Nanoparticles can be targeted passively or actively. Passive targeting exploits the difference between tumor blood vessels and normal blood vessels. Active targeting uses biological molecules antibodies , proteins , DNA and receptor ligands to preferentially target the nanoparticles to the tumor cells.
There are many types of nanoparticle delivery systems, such as silica , polymers , liposomes and magnetic particles. Nanoparticles made of magnetic material can also be used to concentrate agents at tumor sites using an externally applied magnetic field. Electrochemotherapy is the combined treatment in which injection of a chemotherapeutic drug is followed by application of high-voltage electric pulses locally to the tumor. The treatment enables the chemotherapeutic drugs, which otherwise cannot or hardly go through the membrane of cells such as bleomycin and cisplatin , to enter the cancer cells.
Hence, greater effectiveness of antitumor treatment is achieved. Clinical electrochemotherapy has been successfully used for treatment of cutaneous and subcutaneous tumors irrespective of their histological origin. Hyperthermia therapy is heat treatment for cancer that can be a powerful tool when used in combination with chemotherapy thermochemotherapy or radiation for the control of a variety of cancers. The heat can be applied locally to the tumor site, which will dilate blood vessels to the tumor, allowing more chemotherapeutic medication to enter the tumor.
Additionally, the tumor cell membrane will become more porous, further allowing more of the chemotherapeutic medicine to enter the tumor cell. Hyperthermia has also been shown to help prevent or reverse "chemo-resistance. In regard to the potential benefit that drug-resistant cells can be recruited for effective therapy by combining chemotherapy with hyperthermia, it was important to show that chemoresistance against several anticancer drugs e.
Chemotherapy is used in veterinary medicine similar to how it is used in human medicine. From Wikipedia, the free encyclopedia. This article is about cancer treatment. For antimicrobial chemotherapy, see Antimicrobial chemotherapy. For the journal, see Chemotherapy journal. For the journal, see Anti-Cancer Drugs. A woman being treated with docetaxel chemotherapy for breast cancer.
Cold mittens and wine coolers are placed on her hands and feet to reduce harm to her nails.
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Main article: Alkylating antineoplastic agent. Main article: Antimetabolite. Further information: Chemotherapy-induced nausea and vomiting. Further information: Chemotherapy-induced peripheral neuropathy. Main article: List of antineoplastic agents. Main article: History of cancer chemotherapy. Main article: Experimental cancer treatments.
Main article: Electrochemotherapy. The Cochrane Database of Systematic Reviews. Cancer chemotherapy. The Royal Marsden Hospital handbook of cancer chemotherapy: a guide for the multidisciplinary team. Louis, Mo: Elsevier Churchill Livingstone. The Chemotherapy source book. Clinical Cancer Research. Handbook of Cancer Chemotherapy paperback 6th ed. Adjuvant chemotherapy was compared with surgery alone, and dose reduction was used routinely in the case of toxicity or for older patients.
The effect in clinical practice may be more pronounced; it has been estimated that the CMF regimen is used in the community at about half the dose intensity originally shown to be effective [ 2 ]. Since the publication of the Bonadonna study in , many attempts have been made to modify the classical dosage and schedule of the CMF regimen using a variety of strategies which result in a lower dose intensity.
In a recent review of this subject, Goldhirsch observed that such strategies had provided inferior results in both the adjuvant setting and in metastatic breast cancer, and concluded with a recommendation for adherence to the classical dose and schedule [ 21 ]. Adjuvant CMF in node-positive breast cancer: suboptimal doses were associated with poorer outcome.
Used with permission from [ 20 ]. Bonadonna's observations of reduced survival with suboptimal dosing of adjuvant chemotherapy in breast cancer have been confirmed in a randomized controlled trial. Wood et al. Both disease-free and overall survival were longer in women receiving a higher dose of CAF at high or moderate intensities than in women treated with a lower dose at a low intensity Fig. Improved survival with moderate and high-intensity adjuvant CAF cyclophosphamide, doxorubicin, fluorouracil in 1, women with node-positive, stage II breast cancer.
Used with permission from [ 12 ]. In this study, the reduction in RDI was accounted for by treatment delays due to toxicity, as specified by the protocol, rather than dose reductions. In summary, when chemotherapy is being given with curative intent, we believe that it is important to avoid reductions and delays in chemotherapy if the best possible outcome is to be achieved, although this is not possible for all patients. User Name Password Sign In. MaryAnn Foote Amgen Inc. Previous Section Next Section. Figure 1. Breast Cancer One of the most striking examples of the effect of suboptimal doses on outcome was demonstrated in Bonadonna's study in patients with breast cancer receiving 12 cycles of adjuvant CMF cyclophosphamide, methotrexate, 5-fluorouracil [5-FU] chemotherapy [ 15 , 19 , 20 ].
Figure 2. Figure 3. Previous Section. American Society of Clinical Oncology recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol ; 12 : DeVita VT Jr. Principles of cancer management: chemotherapy. Cancer: Principles and Practice of Oncology, 5th edition. Philadelphia: Lippincott-Raven, ; Google Scholar. Skipper HE. Criteria associated with destruction of leukemia and solid tumor cells in animals.
Cancer Res ; 27 : Medline Google Scholar. Norton L. Evolving concepts in the systemic drug therapy of breast cancer. Semin Oncol ; 24 suppl 10 : S3 -S Skipper H. Data and analyses having to do with the influence of dose intensity and duration of treatment single drugs and combinations on lethal toxicity and therapeutic response of experimental neoplasms. Southern Research Institute ; Booklet Hryniuk W, Levine MN.