Part 10

-Anticancer drugs

-Antiviral drugs 

Anti-Cancer Drugs I

Introduction:

The available anticancer drugs have distinct mechanisms of action which may vary in their effects on different types of normal and cancer cells. A single "cure" for cancer has proved elusive since there is not a single type of cancer but as many as 100 different types of cancer. In addition, there are very few demonstrable biochemical differences between cancerous cells and normal cells. For this reason the effectiveness of many anticancer drugs is limited by their toxicity to normal rapidly growing cells in the intestinal and bone marrow areas. A final problem is that cancerous cells which are initially suppressed by a specific drug may develop a resistance to that drug. For this reason cancer chemotherapy may consist of using several drugs in combination for varying lengths of time.

Cancer Chemotherapy:

Chemotherapy drugs, are sometimes feared because of a patient's concern about toxic effects. Their role is to slow and hopefully halt the growth and spread of a cancer. There are three goals associated with the use of the most commonly-used anticancer agents.

1. Damage the DNA of the affected cancer cells.

2. Inhibit the synthesis of new DNA strands to stop the cell from replicating, because the replication of the cell is what allows the tumor to grow.

3. Stop mitosis or the actual splitting of the original cell into two new cells. Stopping mitosis stops cell division (replication) of the cancer and may ultimately halt the progression of the cancer.

Unfortunately, the majority of drugs currently on the market are not specific, which leads to the many common side effects associated with cancer chemotherapy. Because the common approach of all chemotherapy is to decrease the growth rate (cell division) of the cancer cells, the side effects are seen in bodily systems that naturally have a rapid turnover of cells iincluding skin, hair, gastrointestinal, and bone marrow. These healthy, normal cells, also end up damaged by the chemotherapy program.

Catagories of Chemotherapy Drugs:
In general, chemotherapy agents can be divided into three main categories based on their mechanism of action.

Stop the synthesis of pre DNA molecule building blocks:
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 arethe building blocks of DNA and RNA, can not be synthesized. Thus the cells can not replicate because they can nnot make DNA without the nucleotides.

Examples of drugs in this class include 1) methotrexate (Abitrexate®),2) fluorouracil (Adrucil®), 3) hydroxyurea (Hydrea®), and 4) mercaptopurine (Purinethol®).

Directly damage the DNA in the nucleus of the cell:
These agents chemically damage DNA and RNA. They disrupt replication of the DNA and either totally halt replication or cause the manufacture of nonsense DNA or RNA (i.e. the new DNA or RNA does not code for anything useful).

Examples of drugs in this class include cisplatin (Platinol®) and 7) antibiotics - daunorubicin (Cerubidine®), doxorubicin (Adriamycin®), and etoposide (VePesid®).

Effect the synthesis or breakdown of the mitotic spindles:
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 of 8) miotic disrupters include: Vinblastine (Velban®), Vincristine (Oncovin®) and Pacitaxel (Taxol®).

1) Methotrexate:

Methotrexate inhibits folic acid reductase which is responsible for the conversion of folic acid to tetrahydrofolic acid. At two stages in the biosynthesis of purines (adenine and guanine) and at one stage in the synthesis of pyrimidines (thymine, cytosine, and uracil), one-carbon transfer reactions occur which require specific coenzymes synthesized in the cell from tetrahydrofolic acid.

Tetrahydrofolic acid itself is synthesized in the cell from folic acid with the help of an enzyme, folic acid reductase. Methotrexate looks a lot like folic acid to the enzyme, so it binds to it thinking that it is folic acid. In fact, methotrexate looks so good to the enzyme that it binds to it quite strongly and inhibits the enzyme. Thus, DNA synthesis cannot proceed because the coenzymes needed for one-carbon transfer reactions are not produced from tetrahydrofolic acid because there is no tetrahydrofolic acid. Again, without DNA, no cell division.

 2) 5-Fluorouracil:

5-Fluorouracil (5-FU; Adrucil®, Fluorouracil, Efudex®, Fluoroplex®) is an effective pyrimidine antimetabolite. Fluorouracil is synthesized into the nucleotide, 5-fluoro-2-deoxyuridine. This product acts as an antimetabolite by inhibiting the synthesis of 2-deoxythymidine because the carbon - fluorine bond is extremely stable and prevents the addition of a methyl group in the 5-position. The failure to synthesize the thymidine nucleotide results in little or no production of DNA.

Two other similar drugs include: gemcitabine (Gemzar®) and arabinosylcytosine (araC). They all work through similar mechanisms.

Anti-Cancer Drugs II

3) Hydroxyurea:

Hydroxyurea blocks an enzyme which converts the cytosine nucleotide into the deoxy derivative. In addition, DNA synthesis is further inhibited because hydroxyurea blocks the incorporation of the thymidine nucleotide into the DNA strand.

4) Mercaptopurine:

Mercaptopurine, a chemical analog of the purine adenine, inhibits the biosynthesis of adenine nucleotides by acting as an antimetabolite.

In the body, 6-MP is converted to the corresponding ribonucleotide. 6-MP ribonucleotide is a potent inhibitor of the conversion of a compound called inosinic acid to adenine Without adenine, DNA cannot be synthesized.

6-MP also works by being incorporated into nucleic acids as thioguanosine, rendering the resulting nucleic acids (DNA, RNA) unable to direct proper protein synthesis.

5) Thioguanine:

Thioguanine is an antimetabolite in the synthesis of guanine nucleotides.

6) Alkylating Agents:

Alkylating agents involve reactions with guanine in DNA. These drugs add methyl or other alkyl groups onto molecules where they do not belong. This in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA.

In the first mechanism an alkylating agent attaches alkyl groups to DNA bases. This alteration results in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases.

A second mechanism by which alkylating agents cause DNA damage is the formation of cross-bridges, bonds between atoms in the DNA. In this process, two bases are linked together by an alkylating agent that has two DNA binding sites. Cross-linking prevents DNA from being separated for synthesis or transcription.

The third mechanism of action of alkylating agents causes the mispairing of the nucleotides leading to mutations.

There are six groups of alkylating agents: nitrogen mustards; ethylenimes; alkylsulfonates; triazenes; piperazines; and nitrosureas.

Cyclosporamide is a classical example of the role of the host metabolism in the activation of an alkylating agent and is one or the most widely used agents of this class. It was hoped that the cancer cells might posses enzymes capable of accomplishing the cleavage, thus resulting in the selective production of an activated nitrogen mustard in the malignant cells. Compare the top and bottom structures in the graphic on the left.

7) Antibiotics:

A number of antibiotics such as anthracyclines, dactinomycin, bleomycin, adriamycin, mithramycin, bind to DNA and inactivate it. Thus the synthesis of RNA is prevented.

General properties of these drugs include: interaction with DNA in a variety of different ways including intercalation (squeezing between the base pairs), DNA strand breakage and inhibition with the enzyme topoisomerase II. Most of these compounds have been isolated from natural sources and antibiotics. However, they lack the specificity of the antimicrobial antibiotics and thus produce significant toxicity.

The anthracyclines are among the most important antitumor drugs available. Doxorubicin is widely used for the treatment of several solid
tumors while daunorubicin and idarubicin are used exclusively for the treatment of leukemia.

These agents have a number of important effects including: intercalating (squeezing between the base pairs) with DNA affecting many functions of the DNA including DNA and RNA synthesis. Breakage of the DNA strand can also occur by inhibition of the enzyme topoisomerase II.

Doxorubicin &Daunorubicin -

Dactinomycin (Actinomycin D):
At low concentrations dactinomycin inhibits DNA directed RNA synthesis and at higher concentrations DNA synthesis is also inhibited. All types of RNA are affected, but ribosomal RNA is more sensitive. Dactinomycin binds to double stranded DNA , permitting RNA chain initiation but blocking chain elongation. Binding to the DNA depends on the presence of guanine.

 8) Mitotic Disrupters:

Plant alkaloids like vincristine prevent cell division, or mitosis. There are several phases of mitosis, one of which is the metaphase. During metaphase, the cell pulls duplicated DNA chromosomes to either side of the parent cell in structures called "spindles". These spindles ensure that each new cell gets a full set of DNA. Spindles are microtubular fibers formed with the help of the protein "tubulin". Vincristine binds to tubulin, thus preventing the formation of spindles and cell division.

Taxol:

Paclitaxel (taxol) was first isolated from the from the bark of the Pacific Yew (Taxus brevifolia). Docetaxel is a more potent analog that is produced semisynthetically.

In contrast to other microtubule antagonists, taxol disrupts the equilibrium between free tubulin and mircrotubules by shifting it in the direction of assembly, rather than disassembly. As a result, taxol treatment causes both the stabilization of microtubules and the formation of abnormal bundles of microtubules. The net effect is still the disruption of mitosis.

Mechanism of Intercalating Agents:

Intercalating agents wedge between bases along the DNA. The intercalated drug molecules affect the structure of the DNA, preventing polymerase and other DNA binding proteins from functioning properly. The result is prevention of DNA synthesis, inhibition of transcription and induction of mutations.

Examples include: Carboplatin and Cisplatin:
These related drugs covalently bind to DNA with preferential binding to the N-7 position of guanine and adenine. They are able to bind to two different sites on DNA producing cross-links, either intrastrand (within the same DNA molecule which results in inhibition of DNA synthesis and transcription.

Antiviral drugs

Amantadine and Rimantadine

The clinical use of amantadine and rimantadine is restricted to the prophylaxis and early therapy of influenza A virus infections. Influenza prophylaxis is particularly indicated in immunodeficient patients, persons who are allergic to influenza vaccine, unvaccinated house contacts of high-risk patients, and residents of chronic care facilities where an outbreak of influenza A has been recognized. Amantadine is noted for its central nervous system side effects, such as hallucinations and disorientation, which lead, for example, to a risk of falling. Rimantadine causes fewer side effects than amantadine, when used at the same dosage (200 mg/day, perorally). Influenza A virus resistance to both amantadine and rimantadine has been described.

Ribavirin

Although active against ortho- and paramyxoviruses, ribavirin (Virazole) is approved only for the treatment of respiratory syncytial virus (RSV) infection in infants. The drug is administered as a small-particle aerosol (particle diameter, 1 to 3 µm) so that it can reach the lower respiratory tract. Aerosolized ribavirin treatment results in more rapid cessation of viral shedding and resolution of clinical symptoms without signs of systemic toxicity.

Idoxuridine and Trifluridine

Because of their myelosuppressive, mutagenic and teratogenic effects following systemic administration, idoxuridine and trifluridine are only suitable for topical use. Trifluridine is superior to idoxuridine when used in eyedrops for the topical treatment of herpetic keratitis. Idoxuridine can be formulated for topical treatment of herpetic skin lesions.

Vidarabine

Vidarabine (Vira-A) is used for both topical and systemic treatment of herpes simplex virus (HSV) infections. A serious drawback is the poor solubility of this drug in aqueous media, which means that intravenous administration requires a large volume of fluid. When vidarabine and acyclovir were compared for efficacy in treating herpetic encephalitis and varicella-zoster virus (VZV) infection in immunocompromised hosts, acyclovir proved clearly superior to vidarabine. Vidarabine has various toxic side effects (i.e., tremor, ataxia, seizures, myalgia, nausea, vomiting, and diarrhea). Acyclovir is now generally preferred over vidarabine in the treatment of HSV and VZV infections.

Acyclovir, Valaciclovir and Famciclovir

Acyclovir (Zovirax) represents a major breakthrough in the treatment of herpesvirus infections. The main indications for its use are primary genital herpes, herpetic encephalitis and HSV and VZV infections in immunosuppressed patients. It can be used topically, intravenously, or perorally, although its oral absorption is only 20 percent. It offers limited benefit in the topical treatment of recurrent herpes labialis. It is also efficacious in preventing recurrent genital herpes, as well as in preventing HSV infections in renal allograft recipients. Based on an alteration of their thymidine kinase, HSV and VZV may develop resistance to acyclovir, particularly in immunocompromised patients. Valaciclovir (Valtrex) and Famciclovir (Famvir) represent two orally bioavailable compounds for the treatment of HSV and VZV infections. Their main indication is herpes zoster. Valaciclovir and famciclovir act as prodrugs of acyclovir and penciclovir, respectively. Penciclovir acts in a similar fashion as acyclovir, although it would generate higher intracellular levels of the triphosphate form, which is supposed to be the active metabolite for these compounds.

Ganciclovir, Foscarnet

Ganciclovir (Cytovene) is the preferred drug for treating cytomegalovirus (CMV) infections in patients with acquired immune deficiency syndrome (AIDS) or other immunodeficiencies. It has very poor oral bioavailability (3 percent), and, therefore, mostly given intravenously. Of the various clinical manifestations of cytomegalovirus infection in immunosuppressed patients, cytomegalovirus retinitis responds best to ganciclovir therapy, but recurs after treatment is stopped. The most frequent adverse side effects are granulocytopenia (neutropenia) and thrombocytopenia. Foscarnet (Foscavir) is the second drug used in the treatment of CMV infections, particularly CMV retinitis, in immunocompromised patients. It must be given intravenously, and it has proved effective in delaying progression of CMV retinitis compared to untreated controls.

Zidovadine, Didanosine, Zalcitabine and Stavudine

Zidovudine (Retrovir, AZT) is licensed for patients infected with human immunodeficiency virus type 1 or 2 (HIV-1 or -2), the agent of AIDS. It appears to impede progression of the disease, to lower the mortality rate and to diminish the frequency of opportunistic infections. The duration of the beneficial effects may be hampered by the emergence of resistant mutants. AZT is well absorbed orally (60 percent) and readily crosses the blood-brain barrier. Serious side effects, particularly megaloblastic anemia and leukopenia, necessitate withdrawal of the drug in some patients. In addition to zidovudine, three other dideoxynucleosides, viz. didanosine (Videx, DDI), zalcitabine (Hivid, DDC) and stavudine (Zerit, D4T) have been licensed for the treatment of patients with HIV infection. All these compounds act in a similar fashion in that they are targeted at the reverse transcriptase. They all cause toxic side effects, particularly peripheral neuropathy (DDI, DDC and D4T) and pancreatitis (DDI). As these adverse reactions are not overlapping with those of AZT, both DDI and DDC have been used in combination with AZT in attempts to obtain better efficacy with lower toxicity.

Approved antiviral drugs.