A Brief Introduction To Anti-Cancer Drugs

Anti-Cancer drugs are medicines formulated to treat wide range of cancer. Cancer is the uncontrolled growth of cells that interfere with the growth of healthy cells. The usual treatments of Cancer are surgery, chemotherapy (treatment with anticancer drugs), radiation, or some combination of these methods. Anti-Cancer drugs are targeted to control and treat various Cancer like, Breast cancer, Cervical cancer, Small cell lung cancer, Head and Neck cancer, Ovarian cancer, Hodgkin’s and Non-Hodgkin’s lymphoma, Oesteo-sarcoma, Seminomas of testis, Myeloblastic leukemia, Lymphoblastic leukemia etc. The use and application of drugs synthesized or procured from natural or synthetic sources for cancer inhibition and cure is known as “chemotherapy” and the drugs are more commonly named as chemotherapeutic drugs. As stated earlier, cancer can be defined as a state where cells or tissues of the body start to divide uncontrollably and evade the normal cell cycle as a result of which progression of large tumors occur, and the tumorous cells by the mechanism of metastasis may invade the neighboring normal tissues of the body causing serious implications. Keeping this in mind cancer drugs has been designed to slowly act on the cancerous cells and halt their progression by suppressing them through various molecular mechanisms.

Common Mechanism of Action of Anti-Cancer Drugs:

1. They may act by damaging the DNA of cancerous cells. The anticancer drugs cause single strand (SSB) and double strand (DSB) DNA breaks or may lead to manufacture of nonsense DNA or RNA. Examples of drugs in this category include Cisplatin, Mitomycin C, Daunorubicin, Doxorubicin and Etoposide.
2. They inhibit the synthesis of new DNA to stop the cell from replicating because replication of cells leads to growth of tumor. These agents work in a number of different ways. DNA building blocks are folic acid, heterocyclic bases, and nucleotides, which are made naturally within cells. All of these agents work to block some step in the formation of nucleotides or deoxyribonucleotides (necessary for making DNA). When these steps are blocked, the nucleotides, which are the building blocks of DNA and RNA, cannot be synthesized. Thus the cells cannot replicate because they cannot make DNA without the nucleotides. Examples of drugs in this category include methotrexate, fluorouracil, hydroxyurea and mercaptopurine.
3. They stop mitosis or the actual splitting of the original cells into cell into two new cells. Stopping mitosis stops cell division (replication) of the cancer cells and may ultimately halt the progression of the cancer.

Anti-Cancer agents can be divided into following several categories:

*Alkylating agents (e.g., Mitomycin C, Cyclophosphamide),

*Antibiotics which affect nucleic acids (e.g., Doxorubicin, Bleomycin),

*Mitotic inhibitors (e.g., Vincristine, Vinblastine, Taxol),

*Platinum compounds (e.g., Cisplatin),

*Camptothecin derivatives (e.g., Topotecan),

*Antimetabolites (e.g., 5-fluorouracil),

*Biological response modifiers (e.g., Interferon) and

*Hormone therapy (e.g., Tamoxifen).

Description of mechanism of some compounds

* Alkylating Agents (Mitomycin C) and Platinum Antitumor (Cisplatin) Compounds:

The alkylating agents and the platinum antitumor compounds react with electron-rich atoms to form strong chemical bonds. In biological systems the primary cytotoxic reactions of these agents are with the atoms in proteins and DNA. The most important reactions for biological cytoxicity are with components of DNA, and to a lesser extent with RNA and proteins. Mitomycin C which has been efficiently used in the treatment of various cancer like gastric cancer, pancreatic cancer, breast cancer, non-small cell lung cancer, cervical cancer, prostate cancer and bladder cancer was stated to possess a quinone chemical structure which through a cascade of bio-reductive process generates OH . radical of high reactivity which was considered to have potential to directly damage the DNA as well as other biomolecules of cell. Since, free radicals are highly reactive and termed as reactive oxygen species (ROS), they are prone to undergo reduction by oxidation of surrounding molecules (DNA, lipids, proteins). Mitomycin C is a bioreductive alkylating agent, it also damages DNA by cross-linking bases in the same or adjacent strands of DNA principally at the N2 position of the guanine (G) forming monofunctionally and biofunctionally alkylated G-MMC monoadducts and G-MMC-G interstrand and intrastrand cross-links at CpG and GpG sites, respectively which may eventually lead to apoptotic cell death. Various DNA-adducts formed by Mitomycin C has been identified and isolated in different cell types. Mitomycin C has also been reported to activate caspase-3, caspase-8 and caspase-9 mediated apoptosis as well as necrosis.

Cisplatin, also called Cisplatinum and Cisdiamminedichlorido-platinum(II), is a platinum-based cancer chemotherapeutic drug, which has been used in the treatment of various types of cancers, including carcinomas, sarcomas, lymphomas and some germ cell tumors, (e.g., seminomas and germinomas). Cisplatin was the first member of a platinum-based class of therapeutic agents, which now has other members too. It has the powerful property of being an antitumor agent and exerts its effect via interaction with DNA to produce cross-linked DNA adducts that activate checkpoint signaling pathways and thereby induce apoptosis. As early as 1986, East-man suggested DNA to be the major target of Cisplatin. Pinto and Lippard in 1985 forwarded the concept that Cisplatin causes inhibition of DNA synthesis by acting on DNA template rather then on DNA polymerase. The Cis configuration of Cisplatin favors the formation of intra-strand crosslinks in DNA. Upon entering the cell, Cisplatin is spontaneously hydrolyzed to a strongly electrophilic, bifunctional agent that platinates DNA through the positions occupied by chlorine atoms to the N7 position of deoxyguanosine and deoxyadenosine.

* Mitotic inhibitors (e.g., Vincristine, Vinblastine, Taxol):

Mitotic spindle are the fibers which attaches the chromosomes and helps in segregating the chromosomes in daughter cells during cell division. The spindle apparatus includes spindle microtubules, associated proteins and centrioles or asters present at the spindle poles. The vinca alkaloids like Vincristine or Vinblastine principally induce cytotoxicity by disrupting microtubule function, particularly of microtubules that comprise the mitotic spindle apparatus, leading to metaphase arrest and cell death. However, they are also capable of many other biochemical activities that may or may not be related to their effects on microtubules, including inhibiting synthesis of proteins and nucleic acids, elevating oxidized glutathione, altering lipid metabolism and membrane lipids, elevating cyclic adenosine monophosphate (cAMP), and inhibiting calcium-calmodulin-regulated cAMP phosphodiesterase. Many of the effects that do not involve microtubule disruption occur only after treatment with superpharmacological concentrations that are not readily attained in vivo, whereas nanomolar concentrations, which are readily achievable in clinical practice, induce typical antimicrotubule effects. The vinca alkaloids also disrupt the structural integrity of platelets and other cells, which are rich in tubulin. In addition to mitotic disruption, the vinca alkaloids and other antimicrotubule agents perturb cells in nonmitotic cell-cycle phases, which is not surprising because microtubules are involved in many nonmitotic functions.

The vinca alkaloids induce a potent block in mitosis at the metaphase/anaphase transition. Following nuclear envelop breakdown, the vinca alkaloids block mitotic spindle formation and reduce the tension at the kinetochores of the chromosomes. Although chromosomes may condense, they remain scattered in the cells. The chromosomes separate along their lengths, but still remain attached at their centromeres. Mitotic progress is delayed in a metaphase-like state, with chromosomes "stuck" at the spindle poles, unable to move to the spindle equator. The cell-cycle signal to the anaphase-promoting complex, which is required for the cell to transition from metaphase to anaphase, is blocked and apoptotic cell death ensues. Cell-cycle progression in the absence of anaphase or cytokinesis may occur, resulting in chromatin decondensation and formation of multilobed nuclei. Disruption of spindle-microtubule dynamics without microtubule depolymerization ultimately leads to apoptosis, which involves the expression of proapoptotic genes and activation and inactivation of proapoptitoc and antiapoptotic proteins, respectively. The induction of apoptosis, however, does not depend on the presence of an intact TP53 checkpoint. The loss of p21, a protein that controls entry into mitosis at the G2/M checkpoint, increases the sensitivity of tumor cells to both vinca alkaloids and taxanes, which is associated with hastened entry of drug-damaged cells into mitosis.

* Antimetabolites (e.g., 5-fluorouracil):

An antimetabolite is a chemical 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. Antimetabolites can be used in cancer treatment, as they interfere with DNA production and therefore cell division and the growth of tumors. Because cancer cells spend more time dividing than other cells, inhibiting cell division harms tumor cells more than other cells. We now have a proper understanding and knowledge of enzymes and biosynthesis of purine and pyrimidine nucleotide precursors of RNA and DNA.This intricate metabolic reactions works under a complex web of positive-feedback and negative-feedback controls. Most purine or pyrimidine analogs are active only after metabolic activation to the nucleotide form, so these fraudulent nucleotides not only may be incorporated, but also can mimic the natural effector compounds in regulatory pathways. Alternatively, they may deplete critical intermediates, thereby generating enlarged pools of the natural precursors behind a metabolic block, producing effects that can distort the balance of ribonucleoside and deoxyribonucleoside triphosphates. A target of even greater complexity is the incorporation of triphosphates into DNA or RNA and the subsequent modification of these macromolecules. Fluorouracil (5-FU or f5U) (sold under the brand names Adrucil, Carac, Efudix, Efudex and Fluoroplex) is a drug that is a pyrimidine analog which is used in the treatment of cancer. It is an inhibitor and works through irreversible inhibition of thymidylate synthase. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidine, which is a nucleotide required for DNA replication. Thymidylate synthase methylates deoxyuridine monophosphate (dUMP) into thymidine monophosphate (dTMP). Administration of 5-FU causes a scarcity in dTMP, so rapidly dividing cancerous cells undergo cell death via thymineless death.

[Courtesy: HOLLAND-FREI CANCER MEDICINE - 8th Ed. (2010)]

* Camptothecin derivatives (e.g., Topotecan):

Camptothecin is an alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata. This compound selectively inhibits the nuclear enzyme DNA topoisomerase, type I. Several semisynthetic analogs of camptothecin have demonstrated antitumor activity. Camptothecin traps an important cellular enzyme, topoisomerase I, in complexes with DNA. This prevents cancer cell DNA replication and results in the death of the cancer cell. This unique mode of action rekindled interest in developing analogs of camptothecin that were both water soluble and retained anticancer activity. In the mid-1990s, two camptothecin analogs, topotecan and irinotecan, received FDA approval for use against ovarian, lung, breast, and colon cancers

*Hormone therapy (e.g., Tamoxifen):

Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist; hence tamoxifen may be characterized as a mixed agonist/antagonist. It has been the standard endocrine (anti-estrogen) therapy for hormone receptor-positive early breast cancer in pre-menopausal women, although aromatase inhibitors have been proposed. Some breast cancer cells require estrogen to grow. Estrogen binds to and activates the estrogen receptor in these cells. Tamoxifen is metabolized into compounds that also bind to the estrogen receptor but do not activate it. Because of this competitive antagonism, tamoxifen acts like a key broken off in the lock that prevents any other key from being inserted, preventing estrogen from binding to its receptor. Hence breast cancer cell growth is blocked.

Most of the chemotherapeutic drugs are FDA approved but unfortunately generates a very high level of toxicity. The visible toxicity includes nausea, diarrhea, dysentery, alopecia, weakness, fatigue and more seriously toxicity is conferred to the normal cells and genetic material of the cells. The agents most noted for creating cellular damage by initiating free radical oxidants are the alkylating agents, the tumor antibiotics, and the platinum compounds. The agents in these categories demand correct definition concerning interactions with antioxidants supplementation which might reduce effectiveness of chemotherapy. There is also the possibility of adverse interaction between antioxidant treatment and agents that do not act via an oxidative mechanism (e.g., 5-fluorouracil or Tamoxifen).Mitotic spindles serve as molecular railroads with "North and South Poles" in the cell when a cell starts to divide itself into two new cells. These spindles are very important because they help to split the newly copied DNA such that a copy goes to each of the two new cells during cell division. These drugs disrupt the formation of these spindles and therefore interrupt cell division. Examples of drugs in this class are Vinblastine, Vincristine and Pacitaxel.