Classification of antineoplastic agents by their selective toxicities toward oxygenated and hypoxic tumor cells (original) (raw)
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Cancer research, 1990
In order to investigate the effect of environmentally determined conditions on the cytotoxicity of anticancer treatments, Hoechst 33342 dye selected tumor subpopulations were separated after in vivo treatment and plated for single cell colony survival. The 10% brightest cells were assayed as putative normally oxygenated cells and the 20% dimmest as putative hypoxic cells. At single therapeutic doses, cyclophosphamide treatment resulted in the largest differential killing between bright and dim cells (6.3-fold bright greater than dim); 1,3-bis(2-chloroethyl)-1-nitrosourea was 3.2-fold more cytotoxic toward bright cells and carboplatin was 2.4-fold more toxic toward bright cells. Both radiation (10 Gy) and melphalan were 2.2-fold more toxic to bright cells, while cis-diamminedichloroplatinum(II) was 1.8-fold, thiotepa was 1.2-fold and procarbazine was 1.3-fold more toxic to bright cells. Actinomycin D was 3.4-fold more toxic to bright cells. Adriamycin was 2.2-fold, vincristine was 2....
International Journal of Radiation Oncology*Biology*Physics, 1982
DL-152 is toxic to cells of two transplantable mouse tumors. Minimal numbers of surviving tumor cells are seen at 24 and 48 hours following administration of the drug to the tumor bearing mouse, the small fraction of cells surviving at this time (for doses as low as 5 mg/kg) indicates that both hypoxic and aerated cells are killed. For short (one hour) exposures in viva, however, both acutely and chronically hypoxic cells are more sensitive to DL-152 than are their aerated counterparts. For KHT cells growing as lung nodules, DL-152 toxicity is not demonstrable until 11-14 days after initiation of the lung tumor, coinciding with the time at which an hypoxic fraction develops in this model. In vitro experiments using KHT cells in suspension showed certain concentrations of DL-152 to he selectively toxic to hypoxic cells. At higher concentrations both hypoxic and aerated cells were killed by the drug. The combined effect of DG152 and irradiation has been investigated using, as an index of response, the time required for a transplantable tumor to regrow to a given volume after treatment. DL-152 was equally effective in prolonging the period of radiation-induced growth delay when it was given either shortly before or shortly after irradiation. Growth delay attributable to dlrug plus irradiation was greater than would be predicted if the effects of the two modalities were additive. It is concluded that DL-152 has a concentration-dependent specific toxicity for hypoxic cells and that the drug may require a hypoxic milieu to manifest toxicity.
Cancer research, 1986
Solid neoplasms may contain deficient or poorly functional vascular beds, a property that leads to the formation of hypoxic tumor cells, which form a therapeutically resistant cell population within the tumor that is difficult to eradicate by ionizing irradiation and most existing chemotherapeutic agents. As an approach to the therapeutic attack of hypoxic cells, we have measured the cytotoxicity and DNA lesions produced by the bioreductive alkylating agents mitomycin C and porfiromycin, two structurally similar antibiotics, in oxygen-deficient and aerobic cells. Mitomycin C and porfiromycin were preferentially cytotoxic to hypoxic EMT6 cells in culture, with porfiromycin producing a greater differential kill of hypoxic EMT6 cells relative to their oxygenated counterparts than did mitomycin C. Chinese hamster ovary cells were more resistant to these quinone antibiotics; although in this cell line, porfiromycin was significantly more cytotoxic to hypoxic cells than to aerobic cells, ...
Effects of anticancer agents on the respiration of isolated mitochondria and tumor cells
European Journal of Cancer (1965), 1974
A number of anticancer agents of high efficiency and yet considerable toxicity, interact with the bioenergetics and ion transport of not only the target tumor cells, but those of the host organs as well. The possibility that there is a generalized site of toxicity of such agents with the host organ, particularly the heart and liver, has encouraged us to make a more detailed study of the site o faction of respiratory inhibition by a variety of anticaneer drugs selected for this purpose.
Analysis of Antineoplastic Drugs: Clinical Pharmacology and Therapeutic Study
The current study depicts that it is observed the even the slight presence of easily oxidizable substance like thio-urea, ascorbic acid, hydrazine; alcohols etc. interfere in the estimation. In such case higher recovery is obtained because the compound reacts with the reagent. Therefore, the presence of such substances was avoided. Excipients like starch, calcium carbonate, sodium carbonate, cellulose, magnesium tri-silicate, tri-calcium phosphate and gum acacia if present in the pharmaceutical preparations do not interfere in the estimation. Background: Antineoplastic agents are a group of specialized drugs used primarily to treat cancer (the term "neoplastic" refers to cancer cells). The first antineoplastic agents used in the 1940s, were made from either synthetic chemicals or natural plants. Antineoplastic agents are classified by origin and by how they work to destroy cancer cells. Antineoplastic agents can be administered to patients alone or in combination with other antineoplastic drugs. They can also be given before, during or after a patient receives surgery radiation therapy. Antineoplastic agents travel the body and destroy cancer cells.Side effects are expected to occur when treated with these agents, and can include nausea, mouth sores, hair loss, and lowering of the blood counts. Many of the side effects associated with antineoplastic agents occur because chemotherapy treatment destroys the body's normal cells in addition to cancerous cells. Materials and Methods: An aliquot containing 5mg of the sample was taken in a l00mL stoppered conical flask and 5mL of 0.02NNCS reagent, prepared in hydrochloric acid and 5mL of 4N hydrochloric acid was added to it. The reaction mixture was shaken thoroughly and allowed to react for 15minutes at room temperature (25-300C). After the reaction is over 5mL of 5% potassium iodide was added to it. Contents were shaken thoroughly and allowed to react for a minute. The unconsumed NCS was determined iodometrically. A blank experiment was also run under identical conditions using all the reagents except the sample. Results: Methotrexate is a complex compound having six membered heterocyclic ring attached to substituted benzene ring which has got a side chain at para position attached to-NH2 group. The most probable reaction may be chlorination of the benzene ring at ortho position to substituted nitrogen atom. On this basis following reaction product may be postulated.Cytarabine is a derived pyrimidine base nucleus. One of the nitrogen is substituted five membered heterocyclic ring which contain a side chain having a primary hydroxy group. Etoposide is another complex molecule containing two benzene ring along with two five membered rings. One of the ring is highly substituted at ortho and meta position. The other benzene ring has got two five membered substituted cyclic rings. It has also got a glucopyranose ring attached through live membered cyclic ring. It becomes difficult to predict the reaction of this compound with NCS. The central benzene ring has got two active positions at para positions. Therefore chlorination may happen on these available positions. Doxorubicin hydrochloride has got four cyclic rings of which the main molecule is anthraquinone derivative. Conclusion: The current study depicts that it is observed the even the slight presence of easily oxidizable substance like thio-urea, ascorbic acid, hydrazine; alcohols etc. interfere in the estimation. In such case higher recovery is obtained because the compound reacts with the reagent. Therefore, the presence of such substances was avoided. Excipients like starch, calcium carbonate, sodium carbonate, cellulose, magnesium tri-silicate, tri-calcium phosphate and gum acacia if present in the pharmaceutical preparations do not interfere in the estimation.
Antineoplastic Drugs : Treatment Principles and Toxicity
Veterinary World, 2011
The therapy of cancer has improved dramatically during the past half century. This improvement can be traced to a number of factors: a better understanding of cancer's cause and natural history, better technologies for early detection and diagnosis, improved control of primary tumors through surgery and radiation therapy and more effective drugs. The evolution of drug therapy for cancer has progressed rapidly from alkylating agents and antimetabolites to natural products, and most recently, molecular targeted drugs such as imatinib and gefitinib. As our understanding of the biology of cancer improves, new targets for therapy are being identified daily.
2004
Background and Purpose: Hypoxia of clonogenic tumor cells is a major reason for radioresistance and hence local failure in radiotherapy. The objective of the present study was to test the efficacy of the hypoxic cell sensitizer isometronidazole (ISO) during fractionated irradiation in two different human squamous cell carcinomas. Material and Methods: Local control was evaluated for FaDu (radiobiological hypoxic fraction [rHF] 7%) and GL tumors (rHF 0.1%) after single-dose (SD) irradiation under ambient conditions and after 30 fractions within 6 weeks (30 f/6 w). ISO was applied 60 min before SD irradiation at a concentration of 100 mg/kg body weight (b.w.) or 750 mg/kg b.w. in both tumors. During fractionated irradiation, ISO was applied daily 60 min before each fraction (100 mg/kg b.w., in FaDu also 750 mg/kg b.w.). Results: 100 mg/kg b.w. ISO did not improve local control after SD irradiation or 30 f/6 w in both tumor models. Application of 750 mg/kg b.w. ISO significantly decreased the SD-TCD 50 in FaDu tumors (dose-modifying factor [DMF] = 1.2; p = 0.01) but not in the better oxygenated GL tumor. ISO at 750 mg/kg b.w. also significantly improved local control of FaDu tumors after 30 fractions in 6 weeks (DMF = 1.2; p = 0.01), indicating that hypoxic clonogenic cells in FaDu tumors are not only present before start of irradiation but also limit the efficacy of treatment during a fractionated course of radiotherapy. Conclusion: ISO at a concentration of 750 mg/kg b.w. shows an efficacy as a hypoxic cell sensitizer in severely hypoxic FaDu tumors but not in less hypoxic GL tumors. This supports the principle of hypoxic cell sensitization and improvement of local control of hypoxic tumors by nitroimidazole derivatives. However, doses of 750 mg/kg b.w. before each fraction may be difficult to achieve in the clinical situation. This, in light of the fact that other well-tolerable hypoxic cell sensitizers such as nimorazole with clinically proven efficacy at daily oral doses of < 3 g are available, limits the potential usefulness of ISO for radiation oncology.
Toxicities of anticancer drugs and its management
International Journal of Basic & Clinical Pharmacology, 2012
Common toxicities encountered are haematological, gastrointestinal, skin and hair follicle toxicity, nervous system toxicity, local toxicity, metabolic abnormalities, hepatic toxicity, urinary tract toxicity, cardiac toxicity, pulmonary toxicity, gonadal toxicity etc. 3 These toxicities, drugs causing this and management of these toxicities are discussed in subsequent sections of this paper. HAEMATOLOGICAL TOXICITY Peripheral cytopenia from bone marrow suppression is a frequent dose limiting side effect of chemotherapy and can manifest as acute and chronic marrow damage. 4 Chemotherapy may result in the destruction of activity of proliferating haematopoietic precursor cells, leading to deprivation of formed elements, and incidence of life threatening haemorrhage and infection. 5 The drugs causing haematological toxicity are mentioned in Table 1. Management Management varies from dose reduction to treatment for neutropenic sepsis. Patient who develop grade 4 toxicity ABSTRACT One of the characteristics that distinguish anticancer agents from other drugs is the frequency and severity of side effects at therapeutic doses. Most cytotoxic drugs target rapidly multiplying cells and the putative targets are the nucleic acids and their precursors, which are rapidly synthesised during cell division. Many solid tumours have a lower growth fraction than the normal bone marrow, gastro intestinal lining, reticuloendothelial system and gonads. Drugs affect these tissues in a dose dependant manner and there is individual susceptibility also. So toxicities are more frequently associated with these tissues. The side effects may be acute or chronic, self-limited, permanent, mild or potentially life threatening. Management of these side effects is of utmost importance because they affect the treatment, tolerability and overall quality of life. This paper gives an overview of different toxicities of anticancer drugs and its management.