（Anti-Cancer Drugs） By Nohad AlOmari 17/2/2014
INTRODUCTIONCancer: group of diseases characterized by uncontrolled growth and spread of abnormal cells that left untreated may lead to death. Neoplesia: uncontrolled growth of new tissue the product of which is known as tumor & these tumors may be either malignant or benign. Malignant tumors have the capability of invading surrounding tissues and moving to distant location in the body in process called metastasis that characteristic benign tumors does not posses.
Overview
Introduction Malignant disease accounts for a high proportion of deaths in industrialised countries. The treatment of anticancer drug is to give palliation, induce remission and, if possible, cure.Overview
Introduction Cancer occurs after normal cells have been transformed into neoplastic cells through alteration of their genetic material and the abnormal expression of certain genes. Neoplastic cells usually exhibit chromosomal abnormalities and the loss of their differentiated properties. These changes lead to uncontrolled cell division and many result in the invasion of previously unaffected organs, a process called metastasis.Advances in Cancer Chemotherapy
Treatment options of cancer: Surgery: Radiotherapy: Chemotherapy: kill cells (ABs & anticancer agents ) Immunotherapy and Gene therapyAnticancer = antineoplastic Chemotherapy = selective cytotoxicity (difficult!!!!!) Bec. The cell utilized biochemical pathways utilized by normal cells. Inc. knowledge of intercellular & intracellular communication has let to develop of several new agents. (monoclonal antibodies target overproduction of growth factor receptors & tyrosine kinase(TK) inhibitors)
Cell cycle specific agents and Cell cycle Non-specific agents
Cell Cycle Nonspecific Agents (CCNSA) drugs that are active throughout the cell cycle Alkylating Agents Platinum Compounds AntibioticsCell cycle specific agents and Cell cycle Non-specific agents
Cell Cycle Specific Agents (CCSA) drugs that act during a specific phase of the cell cycle S Phase Specific Drug: A.Antimetabolites, Topoisomerase Inhabitors M Phase Specific Drug: Vinca Alkaloids, Taxanes G2 Phase Specific Drug: B.bleomycinAntineoplastic agents can be divided into main four groups:
1.Alkylating agents. 2.Antibiotics. 3. Antimetabolites and natural products, and 4.Tyrosine kinase (TK) inhibitors. 5. Hormones & Gene therapy1.Alkylating Agents
The alkylating agents are a class of drugs that are capable of forming covalent bonds with important biomolecules. There are several potential nucleophilic sites on DNA, which are susceptible to electrophilic attack by an alkylating agent (N-2, N-3, and N-7 of guanine, N-1, N-3, and N-7 of adenine, 0-6 of thymine, N-3 of cytosine). The most important of these for many alkylating agents is the N-7 position of guanine whose nucleophilicity may be enhanced by adjacent guanine residues. Alkylation converts the base to an effective leaving group so that attack by water leads to depurination and the loss of genetic information if the resulting depurination is not repaired by the cell (Scheme 10.1).The general mechanism for alkylation involves nucleophilic attack by —N=, —NH2, —OH, —O—PO3H of DNA and RNA, while additional nucleophiles (—SH, COOH, etc.) present on proteins may also react (Scheme 10.2). Anion formation increases the reactivity of the nucleophile compared with the un-ionized form (—O- is more nucleophilic than OH). Reaction with water is also possible, because it represents the nucleophile in greatest abundance in the body and this becomes more likely as the electrophile becomes more reactive. Reaction involves displacement of a leaving group on the electrophile by the nucleophile. The reactivity of the electrophile is dependent in part on the ability of the leaving group to stabilize a negative charge.
NITROGEN MUSTARDS
Reactivity was reduced such that these compounds could be administered orally. In the case of melphalan, attachment of the mustard functionality to a phenylalanine moiety was not only an attempt to reduce reactivity but also an attempt to increase entry into cancer cells by utilization of carrier-mediated uptake. Melphalan was found to utilize active transport to gain entry into cells, but selective uptake by cancer cells has not been demonstrated. Attachment of more highly electron-withdrawing functionalities was utilized in the case of cyclophosphamide and ifosfamide (Fig. 10.4). In these cases, aziridinium cation formation is not possible until the electron-withdrawing function has been altered.
In the case of cyclophosphamide, it was initially believed that the drug could be selectively activated in cancer cells because they were believed to contain high levels of phosphoramidase enzymes. This would remove the electron-withdrawing phosphoryl function and allow aziridine formation to occur. However, it turned out that the drug was activated by cytochrome P450 (CYP) isozymes CYP2B6 and CYP3A4/5 to give a carbinolamine that could undergo ring opening to give the aldehyde The increased acidity of the aldehyde α-hydrogen facilitates a retro-Michael decomposition(HW??) (Scheme 10.5). The ionized phosphoramide is now electron-releasing via induction and allows aziridinium cation formation to proceed. Acrolein is also formed as a result of this process, which may itself act as an electrophile that has been associated with bladder toxicity. Alternatively, the agent may be inactivated by alcohol dehydrogenase-mediated oxidation of the carbinolamine to give the amide or by further oxidation of the aldehyde intermediate to give the acid by aldehyde dehydrogenase.
BUSULFAN
As an alternative to utilizing aziridines as electrophilic species. Busulfan utilizes two sulfonate functionalities as leaving groups separated by a four-carbon chain that reacts with DNA to primarily form intrastrand cross-link at 5′-GA-3′ sequences. The sulfonates are also subject to displacement by the sulfhydryl functions found in cysteine and glutathione, and metabolic products are formed as a result of nucleophilic attack by these groups to generate sulfonium species along with methane sulfonic acid. This is followed by conversion to tetrahydrothiophene, and further oxidation products are subsequently produced to give the sulfoxide and sulfone. The cyclic sulfone known as sulfolane may be further oxidized to give 3-hydroxysulfolane.ORGANO PLATINUM COMPOUNDS
There are several organometallic compounds based on platinum that play a central role in many cancer treatment protocols.Movement into the tumor cells is accomplished by passive diffusion or carrier-mediated transport. Once inside the tumor cell, the drug encounters a lower chloride concentration and one chloro group is substituted by a water molecule in a process known as aquation. This serves to “trap” the molecule in the cell as a result of ionization. Reaction with DNA occurs preferentially at the N-7 of guanine of two adjacent guanine residues resulting in primarily intra strand cross-links.NITROSOUREAS
These compounds are reasonably stable at pH = 4.5 but undergo both acid and base catalyzed decomposition at lower and higher pH, respectively. There are several pathways of decomposition that are possible for these compounds, but the one that appears to be most important for alkylation of DNA involves abstraction of the NH proton, which is relatively acidic (pKa = 8-9), followed by rearrangement to give an isocyanate and a diazohydroxide. The diazohydroxide, upon protonation followed by loss of water, yields a diazo species that decomposes to a reactive carbocation (Scheme 10.11).The isocyanate functions to carbamylate proteins and RNA, whereas the carbocation is believed to be the agent responsible for DNA alkylation.