Treatment of cancer/Volume II: Antineoplastic drugs

Antineoplastic drugs are drugs that are used to eliminate patient's neoplastic processes. Neoplasms are types of abnormal and excessive growths, called neoplasia, of tissue, a word that is formed from Ancient Greek νέος- neo ("new") and πλάσμα plasma ("formation", "creation").

The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and it persists growing abnormally, even if the original trigger is removed. This abnormal growth usually (but not always) forms a mass. When it forms a mass, it may be called a tumor. ICD-10 classifies neoplasms into four main groups: benign neoplasms, in situ neoplasms, malignant neoplasms, and neoplasms of uncertain or unknown behavior. Malignant neoplasms are also simply known as cancers and are the focus of oncology.

Prior to the abnormal growth of tissue, as neoplasia, cells often undergo an abnormal pattern of growth, such as metaplasia or dysplasia. However, metaplasia or dysplasia does not always progress to neoplasia.

A common group of antineoplastic drugs are cytostatic drugs, medicines that inhibits cell growth by cytostasis (cyto – cell; stasis – stoppage), or the inhibition of cell growth and multiplication. Cytostatic mechanisms and drugs generally occur together with cytotoxic ones. Cytostasis is an important prerequisite for structured multicellular organisms. Without regulation of cell growth and division only unorganized heaps of cells would be possible, other uses of cytostatic drugs are the treatment of skin diseases, treatment of infections and hygienic products. They slow down or stop the growth of specific cells by inhibiting their cell division. They work damaging the DNA of a cell, affecting cells cycle (mitosis) or disturbing the metabolism. Currently are under research many non cytotoxyc antineoplastic drugs.

I.- Drugs that damage cell’s DNA

Alkylating antineoplastic agents

Alkylating agents are used in cancer treatment attaching an alkyl group (CnH2n+1) to DNA. The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring. Since cancer cells, in general, proliferate faster and with less error-correcting than healthy cells, cancer cells are more sensitive to DNA damage—such as being alkylated. Alkylating agents are used to treat several cancers. However, they are also toxic to normal cells (cytotoxic), particularly cells that divide frequently, such as those in the gastrointestinal tract, bone marrow, testicles and ovaries, which can cause loss of fertility. Most of the alkylating agents are also carcinogenic.

Platinum-based antineoplastic

They are coordination complexes of platinum that work crosslinking of DNA as monoadduct, interstrand crosslinks, intrastrand crosslinks or DNA protein crosslinks. Mostly they act on the adjacent N-7 position of guanine, forming a 1, 2 intrastrand crosslink. The resultant crosslinking inhibits DNA repair and/or DNA synthesis in cancer cells. These drugs are used to treat almost half of people receiving chemotherapy for cancer. These drugs can cause a combination of more than 40 specific side effects which include neurotoxicity, which is manifested by peripheral neuropathies including polyneuropathy.

Antimetabolites

Antimetabolites are molecules that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolates that interfere with the use of folic acid; thus, competitive inhibition can occur, and the presence of antimetabolites can have toxic effects on cells, such as halting cell growth and cell division, so these compounds are used as chemotherapy for cancer.

Topoisomerase inhibitor

are chemical compounds that block the action of topoisomerase (topoisomerase I and II), which is a type of enzyme that controls the changes in DNA structure by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle.

It is thought that topoisomerase inhibitors block the ligation step of the cell cycle, generating single and double stranded breaks that harm the integrity of the genome. Introduction of these breaks subsequently leads to apoptosis and cell death. Topoisomerase inhibitors can also function as antibacterial agents. Quinolones (including nalidixic acid and ciprofloxacin) have this function.[4] Quinolones bind to these enzymes and prevent them from decatenation replicating DNA.

Enzymes

Enzimes are molecules that accelerate chemical reactions. Enzymes can be either anabolic or catabolic (can be used to form smaller molecules from a larger molecule or to do the opposite). The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products.

Asparaginase is an enzyme that is used as medication in the form of L-asparaginase is used to treat acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and non-Hodgkin's lymphoma.

The rationale behind asparaginase is that it takes advantage of the fact that acute lymphoblastic leukemia cells and some other suspected tumor cells are unable to synthesize the non-essential amino acid asparagine, whereas normal cells are able to make their own asparagine; thus leukemic cells require high amount of asparagine.[16] These leukemic cells depend on circulating asparagine. Asparaginase, however, catalyzes the conversion of L-asparagine to aspartic acid and ammonia. This deprives the leukemic cell of circulating asparagine, which leads to cell death.

II.- Drugs that act over cell mitosis without modifying cells DNA

Mitotic inhibitor are drugs that inhibits mitosis, or cell division. These drugs disrupt microtubules, which are structures that pull the chromosomes apart when a cell divides. Mitotic inhibitors are used in cancer treatment, because cancer cells are able to grow and eventually spread through the body (metastasize) through continuous mitotic division. Thus, cancer cells are more sensitive to inhibition of mitosis than normal cells. Mitotic inhibitors are also used in cytogenetics (the study of chromosomes), where they stop cell division at a stage where chromosomes can be easily examined.

Mitotic inhibitors are derived from natural substances such as plant alkaloids, and prevent cells from undergoing mitosis by disrupting microtubule polymerization, thus preventing cancerous growth. Microtubules are long, ropelike proteins that extend through the cell and move cellular components around. Microtubules are long polymers made of smaller units (monomers) of the protein tubulin. Microtubules are created during normal cell functions by assembling (polymerizing) tubulin components, and are disassembled when they are no longer needed. One of the important functions of microtubules is to move and separate chromosomes and other components of the cell for cell division (mitosis). Mitotic inhibitors interfere with the assembly and disassembly of tubulin into microtubule polymers. This interrupts cell division, usually during the mitosis (M) phase of the cell cycle when two sets of fully formed chromosomes are supposed to separate into daughter cells.

Vinca alkaloids

Are a set of anti-mitotic and anti-microtubule alkaloid agents originally derived from the periwinkle plant Catharanthus roseus (basionym Vinca rosea), and many species of vinca plants. They block beta-tubulin polymerization in a dividing cell.

Taxanes

Are complex terpenes produced by the plants of the genus Taxus (yews). Originally derived from the Pacific yew tree, they are now synthesized artificially. Their principal mechanism is the disruption of the cell's microtubule function by stabilizing microtubule formation. Microtubules are essential to mitotic reproduction, so through the inactivation of the microtubule function of a cell, taxanes inhibit the cell's division.

III.- Hormonal cytostatic antineoplastic agents

Sex hormone antagonists

These hormones are divided in three categories: antiandrogens, antiestrogens and antiprogestogens.

Antiandrogens

Estrogen-based Estramustine phosphate. EMP acts by a dual mechanism of action: 1) direct cytostatic activity via a number of actions; and 2) as a form of high-dose estrogen therapy via estrogen receptor-mediated antigonadotropic and functional antiandrogenic effects, this produce a suppression of gonadal androgen production and hence circulating levels of androgens such as testosterone; greatly increased levels of sex hormone-binding globulin and hence a decreased fraction of free androgens in the circulation; and direct antiandrogenic actions in prostate cells. Ex: Flutamida, Ciproterona.

Antiestrogens

Also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or inhibiting or suppressing estrogen production. Example: Megestrol acetato.

Another category are the Selective estrogen receptor modulators: Are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists and antagonists (that is, full agonists and silent antagonists) is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues. Ex: Tamoxifen: It has mixed estrogenic and antiestrogenic activity, with its profile of effects differing by tissue.

Antiprogestogens

Corticosteroid-based: Prednimustine, it is used in chemotherapy in the treatment of leukemias and lymphomas. It is the ester formed from two other drugs, prednisolone and chlorambucil.

Aromatase inhibitors

Are a class of drugs used in the treatment of breast cancer in postmenopausal women and gynecomastia in men. Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast tumor tissue. The main source of estrogen is the ovaries in premenopausal women, while in post-menopausal women most of the body's estrogen is produced in peripheral tissues (outside the CNS), and also a few CNS sites in various regions within the brain. Estrogen is produced and acts locally in these tissues, but any circulating estrogen, which exerts systemic estrogenic effects in men and women, is the result of estrogen escaping local metabolism and spreading to the circulatory system.

Aromatase is the enzyme that catalyzes a key aromatization step in the synthesis of estrogen. It converts the enone ring of androgen precursors such as testosterone, to a phenol, completing the synthesis of estrogen. As hormone postive breast and ovarian cancers require estrogen to grow, AIs are taken to either block the production of estrogen or block the action of estrogen on receptors. Ex: Aminoglutemida.

There are two types of aromatase inhibitors approved to treat breast cancer:

Irreversible steroidal inhibitors

Forms a permanent and deactivating bond with the aromatase enzyme. Example: exemestane.

Nonsteroidal inhibitors

inhibit the synthesis of estrogen via reversible competition. Examples: Triazoles anastrozoleand letrozole,

Gonadotropin-releasing hormone (GnRH) analogues

In 1972 Roger Guillemin and Andrew V. Schally discovered Gonadotropin-releasing hormone(GnRH)… this allowed the development of new drugs, among them: GnRH modulators, or GnRH receptor modulator, also known as an LHRH modulator or LHRH receptor, this allowed the development of new drugs.

Examples:

Goserelin: Is a medication which is used to suppress production of the sex hormones (testosterone and estrogen). Leuprorelin: is a gonadotropin-releasing hormone (GnRH) analogue acting as an agonist at pituitary GnRH receptors. Agonism of GnRH receptors initially results in the stimulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion by the anterior pituitary ultimately leading to increased serum estradiol and testosterone levels via the normal physiology of the hypothalamic–pituitary–gonadal axis (HPG axis); however, because propagation of the HPG axis is incumbent upon pulsatile hypothalamic GnRH secretion, pituitary GnRH receptors become desensitised after several weeks of continuous leuprorelin therapy. This protracted downregulation of GnRH receptor activity is the targeted objective of leuprorelin therapy and ultimately results in decreased LH and FSH secretion, leading to hypogonadism and thus a dramatic reduction in estradiol and testosterone levels regardless of sex. In the treatment of prostate cancer, the initial increase in testosterone levels associated with the initiation of leuprorelin therapy is counterproductive to treatment goals. This effect is avoided with concurrent utilisation of 5α-reductase inhibitors, such as finasteride, which function to block the downstream effects of testosterone.

Glucocorticoids

Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebrate animal cell. The name "glucocorticoid" is a portmanteau (glucose + cortex + steroid) and is composed from its role in regulation of glucose metabolism, synthesis in the adrenal cortex, and its steroidal structure (see structure to the right). A less common synonym is glucocorticosteroid. Example: Prednisona.

Cancer immunotherapy

Cancer immunotherapy (sometimes called immuno-oncology) is the artificial stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight cancer. It is an application of the fundamental research of cancer immunology and a growing subspeciality of oncology. It exploits the fact that cancer cells often have tumor antigens, molecules on their surface that can be detected by the antibody proteins of the immune system, binding to them. The tumor antigens are often proteins or other macromolecules (e.g. carbohydrates). Normal antibodies bind to external pathogens, but the modified immunotherapy antibodies bind to the tumor antigens marking and identifying the cancer cells for the immune system to inhibit or kill. In 2018 James Allison and Tasuku Honjo received the Nobel Prize in Physiology or Medicine for their discovery of cancer therapy by inhibition of negative immune regulation.

Cytokines

Are a broad and loose category of small proteins (~5–20 kDa) that are important in cell signaling. Cytokines are peptides, and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrine signaling, paracrine signaling and endocrine signaling as immunomodulating agents. Their definite distinction from hormones is still part of ongoing research. Cytokines used in antineoplastic treatments include the following:

Interleukins

Include Lymphokines.

Monoclonal antibodies (mAb or moAb)

Are antibodies that are made by identical immune cells that are all clones of a unique parent cell. Monoclonal antibodies can have monovalent affinity, in that they bind to the same epitope (the part of an antigen that is recognized by the antibody). Given almost any substance, it is possible to produce monoclonal antibodies that specifically bind to that substance; they can then serve to detect or purify that substance. Monoclonal antibodies that bind only to cancer cell-specific antigens and induce an immune response against the target cancer cell.

MAbs approved by the FDA (for cancer) as of 2005 include the following:

• Alemtuzumab
• Bevacizumab
• Cetuximab
• Gemtuzumab ozogamicin
• Ipilimumab
• Ofatumumab
• Panitumumab
• Pembrolizumab
• Ranibizumab
• Rituximab
• Trastuzumab

IV- Cancer vaccines

Cancer vaccine is a vaccine, that either treats existing cancer or prevents development of a cancer.

a.- Vaccines that treat existing cancer are known as therapeutic cancer vaccines.

Bacillus Calmette–Guérin (BCG) vaccine: Was developed by Albert Calmette and Camille Guérin. The BCG vaccine was first used in humans in 1921. BCG has been one of the most successful immunotherapies. BCG vaccine has been the "standard of care for patients with bladder cancer (NMIBC)" since 1977.

b.- Vaccines that prevents development of a cancer.

Infections are the cause of 17.8% of human cancers, with 11.9% caused by one of seven viruses. These cancers might be easily prevented through vaccination (e.g., papillomavirus vaccines): Human papilloma virus (HPV) vaccines are vaccines that prevent infection by certain types of human papillomavirus: Available vaccines protect against either two, four or nine types of HPV. All vaccines protect against at least HPV types 16 and 18, which cause the greatest risk of cervical cancer. It is estimated that the vaccines may prevent 70% of cervical cancer, 80% of anal cancer, 60% of vaginal cancer, 40% of vulvar cancer and possibly some mouth cancer. They additionally prevent some genital warts, with the vaccines against HPV types 4 and 9 providing greater protection.

Glossary

Antigens (Ag): Are molecules that can induce the production nantibodies (Ab) or are specifically bound by a cell surface version of Ab ~ B cell antigen receptor (BCR), can also refer to any molecule or a linear molecular fragment after processing the native antigen that can be recognized by T-cell receptor (TCR). BCR and TCR are both highly variable antigen receptors diversified by somatic V(D)J recombination. Both T cells and B cells are cellular components of adaptive immunity.

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.

Chemotherapeutic drugs In a broad sense are drugs that impair 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.

Macrophages (Greek: big eaters, from Greek μακρός (makrós) = large, φαγεῖν (phagein) = to eat) are a type of white blood cell, of the immune system, that engulfs and digests cellular debris, foreign substances, microbes, cancer cells, and anything else that does not have the type of proteins specific to healthy body cells on its surface in a process called phagocytosis.

Also see

• Structural_Biochemistry

References

1. The Free Dictionary. Mosby's Medical Dictionary, 8th Edition. © 2009, Elsevier., 2009. Web. 28 Oct. 2012. http://medical-dictionary.thefreedictionary.com/compartment+model.

1. Dhillon, Soraya and Gill, Kiren. "Basic Pharmacokinetics." 28 Oct. 2012. http://www.pharmpress.com/files/docs/clinical_pharmacokinetics_samplechapter.pdf