Antineoplastic agent

Another review covered metabolic studies on cylophosphamide, ifosfamide and trofosfamide. The analytical techniques covered were GC/MS, LC/MS and LC/MS/MS [67]. The same class of drugs has been determined in urine by GC/MS/MS with on-column injection and LC/MS/MS with LLE [68,69]. Chiral derivatisation has been used in conjunction with HPLC to measure the ratio of cyclophosphamide enantiomers [70]. 

Alkyl halides, alkyl sulfonates and other alkylating agents have also been subject to scmtiny in spheres other than pharmaceuticals, such as in environmental analysis. Various approaches have included two-step SPE, derivatisation with trifluoroacetic anhydride followed by GC/MS (for cyclophosphamide and its analogues in sewage water) SPE on surface water to isolate the antineoplastic agents carmustine, chlorambucil, cyclophosphamide and melphalan for LC-UV and LC-fluorescence measurements and derivatisation of alkyl halides and epoxides with 4-nitrothiophenol followed by HPLC-UV detection (claimed to be better than NBP derivatisation). A patent exists for a field test kit for mustard gases in military use based on NBP derivatisation. 

Cisplatin (Platinol, Platinol AQ) Oxaliplatin (Eloxatin) Procarbazine (Matulane) 

Stavudine (Zerit) Telbivudine (Tyzeka) Tenofovir (Viread) Tenofovir/Em tricitabine (Truvada) 

Tipranavir (Aptivus) Zidovudine (Retrovir) Zidovudine Lamivudine (Combivir) 

Ribavirin (Virazole, Copegus) Rimantadine (Flumadine) Telbivudine (Tyzeka) Valacyclovir (Valtrex) Valganciclovir (Valcyte) Zanamivir (Relenza) 

Thiotriethylenephospho-ramide (Thiotepa, Thioplex, Tespa, TSPA) 

Another area in which natural products have had a major impact on longevity and quality of life is in the chemotherapy of cancer. In fact, most major anticancer drugs are derived from plants or microorganisms (see Chapter 62). Examples include bleomycin, doxorubicin, daunorubicin, vincristine, vinblastine, mitomycin, streptozocin, and most recently, additions of paclitaxel (Taxol ), ironotecan (a camptothecin derivative), and etoposide and tenoposide (podophyllo-toxin derivatives). 

The observation that fractions of the rosey periwinkle, Catharanthus rosea, produced severe leukopenia, resulted in the isolation and development of two major anticancer drugs, vincristine and vinblastine. These two complex, dimeric indole-indoline alkaloids are important in the treatment of acute childhood leukemia (vincristine), Hodgkin s disease (vinblastine), and metastatic testicular tumors (vinblastine), and continue to be manufactured today by mass cultivation and processing of their natural source. 

Another important anticancer natural product is camptothecin, an alkaloid derived from the Chinese tree Camptotheca acuminata Descne. A semisynthetic water-soluble derivative of camptothecin known as ironotecan (Topotecin , Campto ) was introduced in Japan in 1994 for the treatment of lung, ovarian, and cervical cancers. Unlike Taxol, camptothecin acts by inhibition of the enzyme topoisomerase I. 

Paclitaxel, camptothecin, vincristine, vinblastine, and other compounds currently under development as potential anticancer drugs (i.e., the bryostatins isolated from marine dinoflagellates) were discovered through a broad-based screening program to identify, using a whole-cell inhibition assay, natural products that are active against a battery of representative cancer cell lines. 

Invention Significance Acryloyl-distamycin-guanidino derivatives are 

Preparation of fV-methyl-4-nitropyrrole-2-carboxyxlic acid chloride 

Thionyl chloride (3.16 mol) was added to a solution of yV- me th y 1 -4 - n itropyrro 1 e-2 -carboxylic acid (1.17 mol) dissolved in 1500 ml toluene, then stirred 3 hours at 100°C, and concentrated. A suspension formed which was stirred 2 hours with cyclohexane at ambient temperature. The mixture was then filtered, dried, and the product isolated in 96% yield. The product was used without further purification. 

Preparation of A,-methyl-4-[(A, -methyl-4-nitro-pyrrolyl-2yl)carbonylamino]-pyrrole-2-carboxylic acid 

The Step 1 product dissolved in 350 ml dioxane was treated with a mixture of the Step 2 product (0.56 mol) and NaHC03 dissolved in 300 ml dioxane/water, 1 1, and the mixture stirred 1 hour at ambient temperature. The solution was diluted with 100 ml water and the pH raised to 3 using 2M HC1. The solution was concentrated and the product isolated in 90% yield. The material was used directly without further purification. 

The terms cancer and neaplaslic disease actually encompass more than 100 different tumors, each with its own unique characteristics. Drugs active again.st a cancer of one ti.ssuc often arc ineffective against cancers of other tissues. Even cancers of the same apparent type respond widely to a particular therapeutic protocol. Consequently, it has been difficult to make progre.ss on a broad front of neoplastic diseases. 

There are cogent reasons why cancer is more difficult to cure than bacterial infections. One is that there an qualitative differences between human and bacterial cells. For example, bacterial cells have distinctive cell walls, and their ribosomes differ from those of human cells. In contrast, the differences between normal and neoplastic human cells are mostly quan- 

The basic differences between cancer cells and normal edh are uncontrolled cell proliferation, decreased cellular differentiation, ability to invade surrounding tissue, and ability ip establish new growth at ectopic sites (metastasis). Conuaiy to popular belief, not all tumor cells proliferate rapidly. Plv-liferation rates vary widely with the cell type. Thus, lymphomas and normal intestinal mucosa both proliferate fasui than. solid tumors. Acute leukemia cells actually prolifemc more slowly than the corresponding precursors in normal bone marrow. 

The cell-kill hypothesis states that the effects of antitumor drugs on tumor cell populations follow first-order kinetics. This means that the number of cells killed is proportional to the dose. Thus, chemotherapy follows an exponential or log-kill model in which a constant proportion, not a constant number, of cancer cells are killed. Ilieoretically. the fractional reductions possible with cancer chemotherapy can never reduce tumor populations to zero. Complete er ica-tion requires another effect, such as the immune response. A modified form of the first-order log-kill hypothesis holds that tumor regressions produced by chemotherapy are de-.scribed by the relative growth fraction present in the tumor at the lime of treatment This idea is consistent with the finding that very small and very large tumors are less responsive than tumors of intermediate size.  

Stem cells arc the cells of origin of u cell line, which maintain the potential to regenerate the cell population and from which the differentiated ccll.s are derived. They arc important in the chemotherapy of human tumors becau.se they must be eradicated completely to effect a cure. Treatments that afford sub.stantial reductions in tumor burdens can prtxluce remissions, but the tumor may recur if. some of the stem cells remain. Their eradication is difficult because many arc in the G phase of the cell cycle.  

Busulfan (Myleran) Carmustine (BCNU) Chlorambucil (Leukeran) Cyclophosphamide (Cytoxan) Hexamethylmelamine (Hexastat) 

Cytarabine Floxuridine (Ara-C) Fludarabine phosphate (5-Fluorodeoxyuridine) Fluorouracil (F-ara-A fludara) 

Dactinomycin (Actinomycin D) Daunorubidn (Daimomycin) Doxorubicin (Adriamycin) Epinibicin 

Idarubicin (Mitomycin C) Mitomycin (Mithramycin) Plicamycin (Paclitaxel) 

Diarrhea abdominal pain migration of ascaris through mouth and nose leukopenia alopecia increased serum transaminase activity Benznidazole 

A few years ago significant palliative results were obtained by chemotherapy in a number of human neoplasma. Today it is, however, possible to list at least certain neoplastic diseases that can be associated with a normal life expectancy after treatment with drugs alone or in combination with other modalities. These neoplasms essentially include carcinoma in women, acute leukemia, Burkitt s lymphoma, Ewing s sarcoma, retinoblastoma in children, lymphosarcoma, Hodgkin s disease, rhabdomyosarcoma, mycosis ftmgoides and testicular carcinoma. 

A neoplasm, or tumour is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissue and continues in the same manner after cessation of the stimuli which have initiated it. 

A malignant tumour grows rapidly and continuously, and even when it has impoverished its host and source of nutrition, it still retains the potentiality for further proliferation. Besides, malignant tumours invade and destroy neighbouring tissues and possess no effective capsule, a malignant tumour readilty ulcerate and tend sooner or later to disseminate and form metastases. 

The causation of neoplasms are many, for instance the genetic factors e.g., retinoblastoma is determined by a Mendelian dominant factor and so are the multiple benign tumours the chemical carcinogens e.g., arsenic, soot, coal tar, petrolemn lubricating oil the polycyclic hydrocarbon carcinogens e.g., 1, 2, 5, 6-dibenzanthracene, 3, 4-benzpyrene. 

As on data nearly ten diflfemet types of neoplasms may be cured with the aid of chemotherapy in patients quite satisfactorily, namely leukemia in children, Hodgakin s disease, Burkitt s lymphoma, Ewing s sarcoma, choriocarcinoma in women, lymphosarcoma, mycosis fimgoides, rhabdomyosarcoma, testicular carcinoma, and retinoblastoma in children. 

Clofarabine (Clolar) Cytarabine [ARA-C] (Cytosar-U) Cytarabine Liposome (DepoCyt) Floxuridine (FUDR) Fludarabine Phosphate (Flamp, Fludara) 

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S. antimycoticus Antinematodal activity Antineoplastic Antineoplastic activity Antineoplastic agent... 

Cancer. Cancer is a cellular malignancy characterized by loss of normal controls resulting in unregulated growth, lack of differentiation, and the abihty to invade local tissues and metastasize. Most cancers are potentially curable, if detected at an early enough stage. The ideal antineoplastic agent would destroy cancer cells without adverse effects or toxicities to normal cells. No such dmg exists. 

One example was reported by Liu and Cheng where a crucial isoflavone intermediate was required to synthesize a series of antineoplastic agents. In the event acetophenone... 

Hydrogenation of the product 147 removes the benzyl protecting groups and at the same time reduces the triazine to its dihydro derivative 148. A roundabout scheme is required for dehydrogenation due to the sensitivity of the intermediates. The product is thus converted to its silyl ether 149 exposure to air results in oxidation and desilylation. There is thus obtained the antineoplastic agent fazarabine (150), also known as ara-A C. 

The antineoplastic agent mitindomide (160) in fact represents the well-known product from irradiation of maleimide in benzene [30]. The activity of this old compound was uncovered by one of the large antitumor screens maintained by the National Cancer Institute, The structure is sufficiently complex and the starting materials sufficiently available to lead one to suspect that the product is still produced photochemically. The product can be rationalized by assuming successive 1,4 and 1,2 additions to benzene. Intermediate 159a involves the 1,4 followed by 1,2 addition intermediate 159b presupposes the steps occur in the reverse order. 

Cancer or neoplastic disease is a genomic disorder of the body s own cells which start to proliferate and metastasize in an uncontrolled fashion that is ultimately detrimental to the individual. Antineoplastic agents are used in conjunction with surgery and radiotherapy to restrain that growth with curative or palliative intention. The domain of antineoplastic chemotherapy is cancer that is disseminated and therefore not amenable to local treatment modalities such as surgery and radiotherapy. 

Antineoplastic Agents. Figure 1 Relationship of cell number, number of cell divisions, and corresponding weight. 

Antineoplastic Agents. Figure 2 Growth curve of tumor cells according to Gompertz. 

Antineoplastic agents that cannot be grouped under subheadings 1-9 include miltefosine which is an alkylphosphocholine that is used to treat skin metastasis of breast cancer, and crispantase which breaks down asparagine to aspartic acid and ammonia. It is active against tumor cells that lack the enzyme asparaginase, such as acute lymphoblastic leukemia cells. Side effects include irritation of the skin in the case of miltefosine and anaphylactic reactions in the case of crispantase. Another recent development is the proteasome inhibitor bortezomib which is used to treat multiple myeloma. 

Cancer treatment is a multimodality treatment, i.e., surgery is combined with radiotherapy and antineoplastic chemotherapy. The latter treatment mode is used mainly for cancers which have disseminated. Different forms of cancer differ in their sensitivity to chemotherapy with antineoplastic agents. The most responsive include lymphomas, leukemias, choriocarcinoma and testicular carcinoma, while solid tumors such as colorectal, pancreatic and squamous cell bronchial carcinomas generally show a poor response. The clinical use of antineoplastic agents is characterized by the following principles. 

The therapeutic ratio of antineoplastic agents, which is defined by the dose necessary to cause a significant anticancer effect divided by the dose effecting significant side effects, is generally low (near to one). 

Patients receiving cytotoxic chemotherapy very often need concomitant administrating of antiemetic therapy. Such protocols will start well in advance of administering the cytotoxic, and last for a reasonable time with regard to pharmacokinetics of the antineoplastic agent. In addition, side effects of antineoplastic therapy are made better tolerable by supportive care. 

Cancer, Molecular Mechanism of Therapy Antineoplastic Agents Alkylating Agents Antimetabolites... 

Folic Acid Vitamin B12 Antineoplastic Agents Antiprotozoal Drugs... 

The epidermal growth factor receptor 2 (HER-2) is a protein found on the surface of cells. Heterodimerization of HER-2 activates the enzyme tyrosine kinase, triggering reactions that cause the cells to grow and multiply. HER-2 is found at abnormally high levels on the surface of many types of cancer cells, which may divide excessively. Antibodies targeting HER-2 (e.g., trastuzumab) are used as antineoplastic agents. 

WO 9 519 994 (CNRS appl. 24.1.1995 F-prior. 25.1.1994). combinations with antineoplastic agents ... 

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