Assignment

on
AntiCancer drug as potential
therapeutics for AIDS ?

Submitted to :
Submitted by :

Dr. Sundip Kumar

Vinod Kumar

Associate proff, Dept of MBGE

Id.no 37137

G.B.P.U.A & T, Pantnagar

Ph.D Biochemistry
 Introduction

In recent years, all other forms of immunodeficiency have been overshadowed by an epidemic of
severe immunodeficiency caused by the infectious agent called human immunodeficiency virus
1, or HIV-1. The disease that HIV-1 causes, acquired immunodeficiency syndrome (AIDS) was
first reported in the United States in 1981 in Los Angeles, New York, and San Francisco.
In the short time since the first cases of the AIDS epidemic were reported, scientists have
identified the viral cause of the illness, the basic modes of transmission, accurate tests for the
presence of infection, and effective drugs that slow or halt the progression of the disease. During
that same period, governments and grassroots organizations around the world were spurred into
action to meet the growing need for AIDS education, counseling, patients’ rights, and clinical
research. AIDS research in the developing world has raised ethical questions pertaining to the
clinical testing of new therapies and potential vaccines.

AIDS is caused by the human immunodeficiency virus (HIV), which attacks and weakens the
body's immune system. The immune system is then unable to fight infection and diseases that
invade the body. The study of virology of HIV has opened the door to the study of the molecular
epidemiology of HIV throughout the world. Nucleoside analogues interfere with nucleotide
metabolism and DNA replication and impede the action of reverse transcriptase, the HIV enzyme
that converts the virus’s genetic material into DNA. During this conversion process, these drugs
incorporate themselves into the structure of the viral DNA, rendering the DNA useless and
preventing it from instructing the infected cell to make additional HIV. The nucleoside analogue
known as azidothymidine (AZT), which became available in 1987, was the first drug approved
by the United States Food and Drug Administration (FDA) to treat AIDS. AZT slows HIV
growth in the body, permitting an increase in the number of CD4 cells, which boosts the immune
system. AZT also prevents transmission of HIV from an infected mother to her newborn. Since
the introduction of AZT, additional nucleoside analogues have been developed, including
didanosine (sold under the trade name Videx), zalcitabine (HIVID), stavudine (Zerit), lamivudine
(Epivir), and abacavir (Ziagen). These drugs are not particularly powerful when used alone, and
often their benefits last for only 6 to 12 months. But when nucleoside analogues are used in
combination with each other, they provide longer-lasting and more effective results.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs), introduced in 1996, use a different

mechanism to block reverse transcriptase. These drugs bind directly to reverse transcriptase,
preventing the enzyme from converting RNA to DNA. Three NNRTIs are available: nevirapine
(Viramune), delavirdine (Rescriptor), and efavirenz (Sustiva). NNRTIs work best when used in
combination with nucleoside analogues.

Cancer Drugs as potential therapeutics for AIDS

Nucleoside analogues used in cancer and anti-viral therapies interfere with nucleotide
metabolism and DNA replication, thus inducing their pharmacological effects. A long-awaited
goal in the understanding of the pharmacological properties of these molecules, that is the
molecular characterization of nucleoside plasma-membrane transporters, has been achieved very
recently. These carrier proteins are encoded by at least two gene families and new isoforms
remain to be identified. Direct demonstration of translocation of these drugs by nucleoside
transporters has already been provided and most of them can inhibit natural nucleoside transport,
probably in a competitive manner. The expression of these genes is clearly tissue-specific and
might depend on the differentiated status of a cell. This is relevant because the sensitivity of a
cell to a drug can depend on the type of nucleoside carrier expressed, and the drug itself might
modulate nucleoside carrier expression. Better knowledge of these will contribute to an
improved design of therapies based on nucleoside derivatives.

The spectrum of drug discovery for HIV centers on an appreciation of vulenerable target in the
life cycle of the virus. The first effective drug against HIV was the reverse transcriptase
inhibitors Azidovudine (zidovudine) or AZT. It was originally was developed as an anticancer
drug but did not prove effective in that capacity. It was licenced as an antiretroviral drug in 1987.
Some anticancer drugs, but not all, inhibit replication of human immunodeficiency virus (HIV)
and thus, exhibit a therapeutic potential. Such drugs, unlike the traditional HIV enzyme
inhibitors, could suppress HIV strains that are resistant to inhibitors of viral enzymes, decrease
proviral burden in vivo, or reduce reservoirs of infection via killing infected cells. Thus, they
may be an effective adjunct therapy or perhaps result in a cure. The incidence of HIV infection
and AIDS mortalities continue to increase worldwide, including the United States and parts of
Africa, with a parallel increase in a number of other manifestations, including AIDS defining
malignancies. The basis for continual spread of HIV presumably in large part stems from the
viral resistance to previously successful drugs and the lack of curative antiretroviral drugs. To
reverse these trends, other approaches for AIDS therapy must be developed. One possibility is
the development of potent anticancer drugs, that exhibit anti-HIV activities.

At least four chemically and pharmacologically distinct classes of anticancer drugs, i.e. certain
cyclin-dependent kinase inhibitors (CDKIs), topoisomerase 1 enzyme (top 1) inhibitors, non-
nucleoside antimetabolites, and estrogen receptor ligands are promising candidates. These drugs,
at high doses are used for cancer therapy; at lower concentrations they exhibit anti-HIV activities
in cultured cells. While the antiretroviral and the anticancer activities of the cdk inhibitor
flavopiridol appear to be mutually exclusive and unrelated in cells and animal model(s) of HIV
disease, the top 1 inhibitor 9-nitrocamptothecin, as well as the cdk-inhibitor roscovitine inhibit
replication of HIV via selective sensitization of HIV-infected cells to apoptosis. In contrast, the
inhibitory effects of these compounds are different from other cancer therapeutics that, at toxic
concentrations, activate HIV either in cultured cells (such as certain ingenol and butyrate
derivatives) and/or in patients (such as the widely used cyclophosmamide and cisplatin). This
quality may lead to the eradication of proviral reservoirs, which is not accomplished by the
currently available antiretroviral drugs.

Protease inhibitors, cripples protease, the enzyme vital to the formation of new HIV. When
these drugs block protease, defective HIV forms that is unable to infect new cells. Protease
inhibitors are more powerful than nucleosides and NNRTIs, producing dramatic decreases in
HIV levels in the blood. This reduced viral load, in turn, enables CD4 cell levels to skyrocket.
The first protease inhibitor, saquinavir (Invirase), was approved in 1995. Since then other
protease inhibitors have been approved, including ritonavir (Norvir), indinavir (Crixivan),
nelfinavir (Viracept), and amprenavir (Agenerase).

Fusion inhibitors prevent the binding or fusion of HIV to CD4 cells. When used with other
antiretroviral medicines, fusion inhibitors can reduce the amount of HIV in the blood and
increase the number of CD4 cells.

The anticancer drug, hydroxyurea may be effective against HIV infection. Hydroxyurea
depletes body cells of an enzyme that is involved in DNA synthesis. HIV cannot replicate
without this enzyme. This strategy to combat HIV infection differs from most earlier approaches
that targeted the virus. The effect of hydroxyurea is enhanced when it is combined with
didanosine (ddI). Preliminary research indicates that this dual therapy produces a greater
decrease in HIV than ddI alone. Combined therapy involves low doses of both drugs, which may
reduce the potential for ddI-associated toxic side effects. The potential therapeutic benefits of
hydroxyurea may encourage AIDS researchers to investigate other anti-cancer drugs.
Hydroxyurea research strengthens international cooperation to develop effective HIV drugs.
Clinical trials of hydroxyurea are underway or planned in France, Italy, and the United States.

References:
Voelker (1995) Rebecca Cancer drug may join the AIDS arsenal, Journal of the American
Medical Association

Reza Sadaie M. ; Mayner Ronald ; Doniger Jay (2004) A novel approach to develop anti-HIV
drugs: adapting non-nucleoside anticancer chemotherapeutics Antiviral research , vol. 61: 1-
18

Claudiu T. Supuran , Angela Casini, Andrea Scozzafava (2003) Protease inhibitors of the
sulfonamide type: Anticancer, antiinflammatory, and antiviral agents , Inc. Med Res Rev, 23, No.
5, 535-558,

Chia-Ling Hung , Jay Doniger , Alessio Palini , Stuart W. Snyder , Michael F. Radonovich , John
N. Brady , Panayotis Pantazis , M. Reza Sadaie 9-Nitrocamptothecin inhibits HIV-1 replication
in human peripheral blood lymphocytes: A potential alternative for HIV-infection/AIDS therapy
J. Med. Virol. 64:238-244, 2001.