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Natural Anticancer drugs and Recent Developments in it

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About Authors:
Kaushal Chovatiya, D.R. Mundhada
Agnihotri College of Pharmacy, Wardha,
Maharashtra, India.

Abstract:
Cancer is the second leading cause of death worldwide. Conventional cancer therapies cause serious side effects and, at best, merely extend the patient’s lifespan by a few years. Cancer control may therefore benefit from the potential that resides in alternative therapies. The demand to utilize alternative concepts or approaches to the treatment of cancer is therefore escalating. There is compelling evidence from epidemiological and experimental studies that highlight the importance of compounds derived from plants “phytochemicals” to reduce the risk of colon cancer and inhibit the development and spread of tumors in experimental animals. More than 25% of drugs used during the last 20 years are directly derived from plants, while the other 25% are chemically altered natural products. Still, only 5-15% of the approximately 250,000 higher plants have ever been investigated for bioactive compounds. The advantage of using such compounds for cancer treatment is their relatively non-toxic nature and availability in an ingestive form. An ideal phytochemical is one that possesses anti-tumor properties with minimal toxicity and has a defined mechanism of action. As compounds that target specific signaling pathways are identified, researchers can envisage novel therapeutic approaches as well as a better understanding of the pathways involved in disease progression. Plant derived compounds have played an important role in the development of several clinically useful anticancer agents. Several anticancer agents including taxol, vinblastine, vincristine and topotecan are in clinical use all over the world. A number of promising agents such as combrestatin, betulinic acid and silvesterol are in clinical or preclinical development.An attempt has been made to review some medicinal plants used for the prevention and treatment of cancer and recent state of development of anticancer drugs regarding Natural Products.

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Reference ID: PHARMATUTOR-ART-1186

Introduction:
“Cancer" is the term we give to a large group of diseases that vary in type and location but have one thing in common: abnormal cells growing out of control.” Under normal circumstances the number and growth of all our cells is a highly controlled mechanism. But when the control signals in one of these cells goes wrong, and its life cycle becomes disturbed, it divides and divides. It continues multiplying uncontrollably, and the result of this accumulation of abnormal cells is a mass of cells called a "tumor". A tumor can be either benign (do not spread to other part of body) or malignant (spreads to other parts of body).There are particularly two important families of genes related to cancer. Oncogenesare mutated forms of genes that cause normal cells to grow out of control and become cancer cells. They are mutations of certain normal genes of the cell called protooncogenes. Proto-oncogenes are the genes that normally control how often a cell divides and the degree to which it differentiates (or specializes).Tumor suppressor genesare normal genes that slow down cell division, repair DNA errors, and tell cells when to die (a process known as apoptosis or programmed cell death). When tumor suppressor genes don’t work properly, cells can grow out of control, which can lead to cancer.

 Major  types  of  cancer:

Prostate Cancer
Breast Cancer
Bladder Cancers
Colorectal Cancers
Brain Tumours
Soft Tissue Sarcomas
Germ Cell Tumours
Retinoblastoma
Kidney Cancers
Lung Cancer
Liver Cancer
And Others

The most common cancer risk factors are:

  • Genetic predisposition-- Certain types of cancer, such as colon and breast cancer, often run in families. It is only the predisposition to cancer that is inherited. Other non-genetic (e.g. environmental) factors must be present for the cancer to develop. Having a family history of cancer does not necessarily mean you will develop cancer, but does however mean that you are at a higher risk. Knowing the risk factors and managing them can help prevent cancer.
  • Estrogen exposure (women)-- A woman is at increased risk for some gynecological cancers (e.g. breast or uterine cancer) if her system is exposed to too much estrogen, as this stimulates cell proliferation in these tissues. Factors that contribute to higher estrogen exposure include early menstruation and late menopause. The risk is reduced in women who have had a baby before the age of 35. Other factors that can reduce the risk include regular exercise and a low-fat diet.
  • Ionizing radiation-- Overexposure to ionizing radiation, such as X rays and nuclear radiation, can cause DNA injury that may lead to cancer.
  • Ultraviolet radiationis the radiation from the sun. Ultraviolet B (UVB) rays damage cell DNA and cause 90 percent of all skin cancers. Prevention involves reducing sun exposure, wearing protective clothing and applying a sunscreen with a high SPF (Sun Protection Factor) number.
  • Carcinogenic chemicals-- Chemical carcinogens such as asbestos, benzene, formaldehyde, and diesel exhaust are dangerous in high concentrations.
  • Tobacco smoke-- Smoking causes 30 percent of all cancer deaths in the United States, making tobacco smoke the single most lethal carcinogen. Smoking can cause cancers in the lungs and other organs. The best way to lower the risk of lung and other cancers is to quit smoking, or never start, and to avoid exposure to secondhand smoke if you are a non-smoker.
  • Alcohol-- People who drink alcohol heavily have a higher risk of mouth, throat, esophagus, stomach, and liver cancer.
  • Carcinogenic foods-- There are certain foods that contain carcinogens. Foods that should be limited include salted, pickled, and smoked foods, such as pickles or smoked fish, and meats treated with nitrites. Foods that should be eliminated from the diet include meats that have been charred over a grill, as the charred area is carcinogenic. Taking Vitamin C, either through the diet or by supplementation, may protect against the cancer-causing effects of carcinogenic foods.
  • Unhealthy diet-- A diet high in saturated fat (especially from red meat) is associated with several different types of cancer, including cancer of the colon, rectum, and prostate gland. Risk can be reduced by reducing dietary fat in the diet, and by eating more soy-based foods, fiber, fruit and vegetables.
  • Free radicalsare dangerous, highly reactive chemical compounds that can damage DNA and lead to cancer. They can be generated in a number of ways, including oxidation of polyunsaturated fats. Antioxidants (such as Vitamin A and C) taken through supplementation, or a diet high in yellow and orange fruits and vegetables, can reduce the risk.

Treatment Options: There are a number of treatment options available for cancer. Treatments plans are developed depending on the type of cancer, its location, the extent of the cancer and the stage at which it is diagnosed, and the health and well-being of the patient. Treatment may be one or more of several different therapies.

  • Chemotherapyis the use of anti-cancer of drugs. Anti-cancer drugs destroy cancer cells by stopping growth or multiplication at some point in their life cycles. Drugs may be administered intravenously (into a vein), orally (by mouth), by injection into a muscle, topically (applied to the skin) or in other ways, depending on the drug and the type of cancer. Chemotherapy is often given in cycles of alternating treatment and rest periods.
  • Radiation Therapy is the treatment of cancer and other diseases with ionizing radiation. Ionizing radiation destroys cells, or the genetic material of cells, in the area being treated, thereby making it impossible for these cells to continue to grow.
  • Surgery involves removal of the tumor. Sometimes, surrounding tissue and lymph nodes are also removed. Surgery can be performed using conventional instruments or laser.
  • Hormone Therapy is the use of hormones to change the way hormones in the body help cancers to grow.
  • Biological Therapy (Immunotherapy) makes use of the body's immune system, either directly or indirectly, to fight cancer and lessen the side effects that may be caused by some other cancer treatments.
  • Alternative and Complementary Therapy - includes acupuncture and homeopathy.
  • Nano Technology: New technology for producing materials that form extremely tiny particles is leading to very promising imaging tests that can more accurately show the location of tumors. It also is aiding the development of new ways to deliver drugs more specifically and effectively to cancer cells.
  • Robotic Surgery: This term refers to manipulation of surgical instruments remotely by robot arms and other devices controlled by a surgeon. Robotic systems have been used for several types of cancer surgery; radical prostatectomy is among the most common uses in surgical oncology. As mechanical and computer technology improve, some researchers expect future systems will be able to remove tumors more completely and with less surgical trauma.

·         RNA expression profiling and proteomics:RNA expression profiling lets scientists determine relative amounts of hundreds or even thousands of RNA molecules at one time. Knowing what proteins or RNA molecules are present in cells can tell scientists a lot about how the cell is behaving. In cancer, it can help distinguish more aggressive cancers from less aggressive ones, and can often help predict which drugs the tumor is likely to respond to.

·         Proteomic methods are also being tested for cancer screening. For most types of cancer, measuring the amount of one protein in the blood is not very good at finding early cancers. But researchers are hopeful that comparing the relative amounts of many proteins may be more useful, and that knowing certain proteins are abnormally abundant and others are less abundant can provide accurate, useful information about cancer treatment and its outcomes. This is an exciting area of research and early results in lung and colorectal cancer studies have been promising.

Summary: 
Natural Products, especially plants, have been used for the treatment of various diseases for thousands of years. Terrestrial plants have been used as medicines in Egypt, China, India and Greece from ancient time and an impressive number of modern drugs have been developed from them. The first written records on the medicinal uses of plants appeared in about 2600 BC from the Sumerians and Akkaidians.[1] The “Ebers Papyrus”, the best known Egyptian pharmaceutical record, which documented over 700 drugs, represents the history of Egyptian medicine dated from 1500 BC. The Chinese Materia Medica, which describes more than 600 medicinal plants, has been well documented with the first record dating from about 1100 BC.[2] Documentation of the Ayurvedic system recorded in Susruta and Charaka dates from about 1000 BC.[3] The Greeks also contributed substantially to the rational development of the herbal drugs. Dioscorides, the Greek physician (100 A.D.), described in his work “De Materia Medica” more than 600 medicinal plants. Phytochemicals have been proposed to offer protection against a variety of chronic ailments including cardiovascular diseases, obesity, diabetes, and cancer. As for cancer protection, it has been estimated that diets rich in phytochemicals can reduce cancer risk by 20%.The compounds that are responsible for medicinal property of the drug are usually secondary metabolites. Plant natural product chemistry has played an active role in generating a significant number of drug candidate compounds in a drug discovery program. Recently, it has been reported in the literature that approximately 49 % of 877 small molecules that were introduced as new pharmaceuticals between 1981 and 2002 by New Chemicals Entities were either natural products or semi-synthetic analogs or synthetic products based on natural product models.

Plants have a long history of use in the treatment of cancer. Hartwell, in his review of plants used against cancer, lists more than 3000 plant species that have reportedly been used in the treatment of cancer. It is significant that over 60% of currently used anticancer agents are derived in one way or another from natural sources, including plants, marine organisms and micro-organisms. Indeed, molecules derived from natural sources (so called natural products), including plants, marine organisms and micro-organisms have played and continue to play, a dominant role in the discovery of leads for the development of conventional drugs for the treatment of most human diseases. The search for anti-cancer agents from plant sources started in earnest in the 1950s with the discovery and development of the vinca alkaloids, vinblastine and vincristine, and the isolation of the cytotoxic podophyllotoxins. These discoveries prompted the United States National Cancer Institute (NCI) to initiate an extensive plant collection program in 1960. This led to the discovery of many novel chemotypes showing a range of cytotoxic activities, including the taxanes and camptothecins.[4]

 Cancer, after cardiovascular disease, is the second leading cause of death.[5,6] Worldwide about 10 million people per year are diagnosed with cancer and more than 6 million die of the disease and over 22 million people in the world are cancer patients.[7] When cancer is diagnosed, therapists face a formidable range of challenges. Treatment usually consists of various combinations of surgery, radiation therapy, and chemotherapy but despite these therapeutic options, cancer remains associated with high mortality. Natural and some synthetic compounds can prevent, suppress, or reverse the progression of cancer. Although tumors have traditionally been treated with chemotherapeutic agents, the advents of compounds which prevent malignancies represent an emerging field and offer new options.[8] Cancer is a complex disease that is normally associated with a wide range of escalating effects both at the molecular and cellular levels. It therefore seems unlikely that chemoprevention follows simplistic rules and formulations. The old saying "Prevention is always better than cure" is particularly true in the case of cancer where a cure, if at all possible, is associated with high cytotoxic loads and/or invasive procedures. With our growing understanding of the molecular etiology of cancer, it has become apparent that strategies which limit DNA damage and/or increase the probability of DNA repair by inhibiting aberrant proliferation will decrease cancer incidence.[9] Investigators have identified approximately 400 drugs, vitamins, hormones and other agents that might help in preventing cancer. Clinical trials are underway to investigate an increasing number of agents. Cancer is the abnormal growth of cells in our bodies that can lead to death. Cancer cells usually invade and destroy normal cells. These cells are born due to imbalance in the body and by correcting this imbalance, the cancer may be treated. Billions of dollars have been spent on cancer research and yet we do not understand exactly what cancer is.[10] Most of these trials involve healthy people with a higher than average risk of cancer. Despite the tremendous advancements in the understanding and treatment of cancer, there is no sure fire cure for a variety of cancers to date. Therefore, natural protection against cancer has recently been receiving a great deal of attention not only from cancer patients but, surprisingly, from physicians as well. The major causes of cancer are smoking, dietary imbalances, hormones and chronic infections leading to chronic inflammation.[11] Breast cancer is the most common form of cancer in women worldwide.[12] Amongst South African women, breast cancer is likely to develop in one out of every 31 women in the country. Colon cancer is the second most common cause of cancer deaths in the US. Prostate cancer is the most frequently diagnosed cancer among men in the US, second to skin cancer with an estimated 180,000 new cases and 37,000 deaths expected by American Cancer Society each year.[13] Plants have been used for treating various diseases of human beings and animals since time immemorial. They maintain the health and vitality of individuals, and also cure diseases, including cancer without causing toxicity. More than 50% of all modern drugs in clinical use are natural products, many of which have the ability to control cancer cells. A recent survey shows that more than 60% of cancer patients use vitamins or herbs as therapy.[14,15] These plants are used against various types of tumors/cancers such as sarcoma, lymphoma, carcinoma and leukemia. Many of these medicinal plants have been found effective in experimental and clinical cases of cancers. Attempts are being made to isolate active constituents from natural sources that could be used to treat this very serious illness.

The first agents to advance into clinical use were the isolation of the vinca alkaloids, vinblastine and vincristine from the Madagascar periwinkle, Catharanthus roseus (Apo-cynaceae) introduced a new era of the use of plant material as anticancer agents. They were the first agents to advance into clinical use for the treatment of cancer. Vinblastine and vincristine are primarily used in combination with other cancer chemotherapeutic drugs for the treatment of a variety of cancers, including leukemias, lymphomas, advanced testicular cancer, breast and lung cancers, and Kaposi’s sarcoma. The discovery of paclitaxel from the bark of the Pacific Yew, Taxus brevifolia Nutt. (Taxaceae), is another evidence of the success in natural product drug discovery. Various parts of Taxus brevifolia and other Taxus species (e.g., Taxus Canadensis, Taxus baccata ) have been used by several Native American Tribes for the treatment of some noncancerous cases.[16] Taxus baccata was reported to use in the Indian Ayurvedic medicine for the treatment of cancer. Paclitaxel is significantly active against ovarian cancer, advanced breast cancer, small and non-small cell lung cancer. Camptothecin, isolated from the Chinese ornamental tree Camptotheca acuminate (Nyssaceae), was advanced to clinical trials by NCI in the 1970s but was dropped because of severe bladder toxicity. Topotecan and irinotecan are semi-synthetic derivatives of camptothecin and are used for the treatment of ovarian and small cell lung cancers, and colorectal cancers, respectively.[17,18] Epipodophyllotoxin is an isomer of podophyllotoxin which was isolated as the active antitumor agent from the roots of Podophyllum species, Podophyllum peltatum and Podophyllum emodi (Berberidaceae). Etoposide and teniposide are two semi-synthetic derivatives of epipodophyllotoxin and are used in the treatment of lymphomas and bronchial and testicular cancers.[19] Homoharringtonine isolated from the Chinese tree Cephalotaxus harringtonia (Cephalotaxaceae), is another plantderived agent in clinical use.[20] Combretastatins were isolated from the bark of the South African tree Combretum caffrum (Combretaceae). Combretastatin is active against colon, lung and leukemia cancers and it is expected that this molecule is the most cytotoxic phytomolecule isolated so far.[21,22] Betulinic acid, a pentacyclic triterpene, is a common secondary metabolite of plants, primarily from Betula species (Betulaceae).[23] Betulinic acid was isolated from Zizyphus species, e.g. Zizyphus mauritiana, Zizyphus rugosa and Zizyphus oenoplia and displayed selective cytotoxicity against human melanoma cell lines. Silvestrol was first isolated from the fruits of Aglaila sylvestre (Meliaceae). Silvestrol exhibited cytotoxicity against lung and breast cancer cell lines.[24] The Podophyllum species (Podophyllaceae), Podophyllum peltatum (commonly known as the American mandrake or Mayapple), and Podophyllum emodii from the Indian subcontinent, have a long history of medicinal use, including the treatment of skin cancers and warts. Podophyllum peltatum was used by the Penobscot Native Americans of Maine for the treatment of cancer. Camptothecin isolated from Camptotheca acuminata (Nyssaceae), also known as tree of joy in China is a possible source of steroidal precursors for the production of cortisone. The extract of C. acuminata was the only one of 1000 of the plant extracts tested for anti-tumor activity which showed efficacy and camptothecin was isolated as an active constituent. Other plant derived agents in clinical use are homoharringtonine isolated from the Chinese tree, Cephalotaxus harringtonia (Cephalotaxaceae), and elliptinium, a derivative of ellipticine isolated from species of several genera of the Apocynaceae family including Bleekeria vitensis, a Fijian medicinal plant with reputed anti-cancer properties. Several Terminalia species have reportedly been used in the treatment of cancer. The combretastatins are a family of stilbenes which act as anti-angiogenic agents causing vascular shutdown in tumors and resulting in tumor necrosis.[25] Species of the genus Tabebuia (Bignoniaceae) have a history of use in the Amazonian region for the treatment of several diseases including syphilis, fevers, malaria, cutaneous infections and stomach disorders. Claims for clinical efficacy in the treatment of cancers started in the 1960s, particularly in Brazil and these led to widespread sales of the stem bark and trunk wood of Tabebuia impetiginosa, Tabebuia rosea and Tabebuia serratifolia in health food stores under various names such as pau d’arco or lapacho. They possess numerous bioactive compounds, but the naphthaquinones particularly lapachol and β-lapachone have received most attention. Lapachol showed significant in vivo anti-tumor activity in some early mouse models. Dragon's blood is the popular name for a dark red viscous sap produced by Croton lechleri. This herb is used in folk medicine as an anti-inflammatory, antimicrobial and anticancer.[26-28] Crude extracts from plants like Colubrina macrocarpa, Hemiangium excelsum and Acacia pennatula have been shown to possess a selective cytotoxic activity against human tumor cells.[29] In the Palestinian and Israeli territories, extracts of Teucrium polium and Pistacia lentiscus, among others are known to treat liver disease, jaundice, diabetes, fertility problems and cancer.[30] In Saudi Arabia, aerial parts of Commiphora opobalsamum are commonly used to treat various diseases. However, its potential use in stomach problems and cancer has been reported only recently. Historic medicinal practice used Cat's Claw also known Uncaria tomentosa, as an effective treatment for several health disorders which include chronic inflammation, gastrointestinal dysfunction such as ulcers, tumors and infections. The efficacy of Cat's Claw was originally believed to be due to the presence of oxindole alkaloids. Some Astragalus species are used to treat leukemia and promote wound healing.[31] Chinese medicinal herb Paris polyphylla has been used to treat liver cancer in China for many years and has been reported as a potent anticancer agent that can overcome drug resistance. Salvia officinalis is the most popular herbal remedy in the Middle East to treat common health complications. Salvia species (Labiatae) are known for their antitumor effects.[32] Phytochemically, the whole plant contains several antioxidants that protect against cellular peroxidative damage. Lantana camara possesses several medicinal properties and is commonly used in folk medicine for its antipyretic, antimicrobial and antimutagenic properties.[33] Solanum nigrum is a common herb that grows wildly and abundantly in open fields. It has been used in traditional folk medicine because of its diuretic and antipyretic effects. More specifically, it has been used for a long time in oriental medicine to cure inflammation, edema, mastitis and hepatic cancer.[34]

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Terrestrial Sources
Plants have a long history of use in the treatment of cancer, though many of the claims for the efficacy of such treatment should be viewed with some skepticism because cancer, as a specific disease entity, is likely to be poorly defined in terms of folklore and traditional medicine.9,10 Some plant anticancer drugs in clinical use or development are listed in Tables  Micro-organisms are a prolific source of structurally diverse bioactive metabolites and have yielded some of the most important products of the pharmaceutical industry. These include antibacterial agents, such as the penicillins (from Penicillium species), cephalosporins (from Cephalosporium acremonium), aminoglycosides, tetracyclines, and other polyketides of many structural types (from the Actinomycetales); immunosuppressive agents, such as the cyclosporins (from Trichoderma and Tolypocladium species) and rapamycin (from Streptomyces species); cholesterollowering agents, such as mevastatin (compactin; from Penicillium species) and lovastatin (from Aspergillus species); and anthelmintics and antiparasitic drugs, such as the ivermectins (from Streptomyces species). Antitumor antibiotics are among the most important of the cancer chemotherapeutic agents. Some clinically useful drugs and agents in development are listed in Table 1.

Table 1. Representative Plant-Derived Drugs in Clinical Use or Development

Drug Class

Example

Source Plant

Collection/Source Region

Development
Stage

Vinca alkaloids*

Vinblastine, vincristine,

Vinorelbine

Catharanthus

 roseus

The Philippines,

Jamaica, Madagascar

Clinical use

Lignans*

Etoposide, teniposide

Podophyllum

species

Eastern United States,

 Himalayas

Clinical use

Taxanes*

Paclitaxel, docetaxel

Taxus species

Northwest United

States, Europe

Clinical use

 

Camptothecins*

Topotecan, irinotecan HCl

Camptotheca

acuminata

China

Clinical use

Cephalotaxanes

Homoharringtonine

Cephalotaxus

harringtonia

China

Clinical trials

Flavones

Flavopiridol (synthetic based

 on rohutikine)

Dysoxylum

binectariferum

India

Clinical trials

Stilbenes*

Combretastatin prodrug

(AVE8062A)

Combretum

 caffrum

South Africa

Clinical Trials

Table 2. Representative Microbial-Derived Anticancer Drugs in Clinical Use and Development

Drug Class Example Source Organism Development Stage
Anthracyclines* Daunomycin, doxorubicin Streptomyces species Clinical use
Glycopeptides Bleomycins A2 and B2 Streptomyces verticillus Clinical use
Peptolides Dactinomycin Streptomyces species Clinical use
Mitosanes Mitomycin Streptomyces species Clinical use
Rapamycins* RAD001 Streptomyces species Phase I
Staurosporins* UCN-01, CEP-751 Streptomyces species Phase I, II
Epothilones* EPO906 (epothilone B) Sorangium cellulosum Phase I, II
Cryptophycins Cryptophycin-52 (synthetic) Nostoc species              cyanobac  (cyanobacteria) Phase I

Marine Sources
The world’s oceans, covering more than 70% of the earth’s surface, represent an enormous resource for the discovery of potential chemotherapeutic agents. Of the 33 animal phyla listed by Margulis and Schwartz,12 32 are represented in aquatic environments, with 15 being exclusively marine and 17 being both marine and nonmarine (with five of these having _ 95% of their species only in marine environments), and only one, Onychophora, is exclusively nonmarine. Before the development of reliable scuba-diving techniques some 40 years ago, the collection of marine organisms was limited to those obtainable by skin diving. Subsequently, depths from approximately 10 feet to 120 feet became routinely attainable, and the marine environment has been increasingly explored as a source of novel bioactive agents. The marine environment has proved to be a prolific source of structurally novel bioactive agents, and several have advanced to clinical development as potential anticancer agents.10,11,15 The interest in nature as a source of potential chemotherapeutic agents continues. An analysis of the number and sources of anticancer and anti-infective agents, reported mainly in the annual reports of Medicinal Chemistry from 1984 to 199 covering the years 1983 to 1994, indicates that more than 60% of the approved drugs developed in these disease areas can trace their lineage back to a natural product structure.

Table 3. Current Marine Organism–Derived Anticancer Drugs in Development

Drug Name

Source Organism (type)

Collection Region

Development Stage

Aplidine

Aplidium albicans (tunicate)

Mediterranean sea

Phase I, II

Bengamide analog

Jaspis species (sponge)

Fiji

Phase I

Bryostatin 1

Bugula neritina (bryozoan)

Gulf of California

Phase II

Discodermolide

Discodermia dissoluta (sponge)

Caribbean sea

Phase I

Dolastatin 10

Dolabella auricularia (mollusk)

Indian Ocean

Phase I

Ecteinascidin 743

Ecteinascidia turbinata ( tunicate)

Caribbean Sea

Phase II, III

Squalamine

Squalus acanthias (dogfish shark)

Atlantic Ocean

Phase II

Kahalahide F

Elysia rubefescens (mollusk)

Hawaii

Phase I, II

Halichondrin B analog

Lissodendoryx species (sponge)

New Zealand

Phase I

Hemiasterlin analog*

Cymbastella species (sponge)

Papua New Guinea

Phase I

Isogranulatimide*

Didemnum granulatum (tunicate)

Brazil

Phase I

*Several semisynthetic analogs are earlier in development.

Recently invented natural drug therapies as anticancer treatment

BRITISH FLOWERS ARE THE THE SOURCE OF NEW ANTICANCER DRUG:

Researchers are poised to start clinical trials with a new "smart bomb" treatment, derived from the flower, targeted specifically at tumours. The treatment, called colchicine, was able to slow the growth of and even completely "kill" a range of different cancers, in experiments with mice.  The research was highlighted at the British Science Festival in Bradford. The team behind it, from the Institute for Cancer Therapeutics (ICT) at the University of Bradford, has published the work in the journal Cancer Research. The native British Autumn crocus, otherwise known as "meadow saffron" or "naked lady", is recorded in early herbal guides as a treatment for inflammation. This is because it contains the potent chemical colchicine, which is known to have medicinal properties, including anti-cancer effects. But colchicine is toxic to other tissues in the body, as well as cancer, so until now its use has been limited. The researchers at ICT have now altered the colchicine molecule so it is inactive in the body until it reaches the tumour.  Once there, the chemical becomes active and breaks up the blood vessels supplying the tumour, effectively starving it.  This effect is made possible because of enzymes that all tumours produce, whose usual function is to break down the normal cells nearby, allowing the tumour to spread. The modified colchicine molecule has a protein attached to it that makes it harmless. But the tumour enzyme specifically targets the protein and removes it. The colchicine is then activated, and the process of breaking down blood vessels and starving the cancerous cells begins.  Because the enzyme necessary to activate the toxic colchicine is produced only by solid tumours, it may be possible to treat cancers effectively with virtually no side effects to the rest of the body. The researchers report having tested the effectiveness of this therapy at treating tumours in mice. The treatment has reportedly been tested on five different types of cancer in the laboratory, including breast, colon, lung, sarcoma and prostate. These tests have reportedly been successful to varying degrees, with no adverse effects reported. The researchers report a greater than “70% cure rate after a single dose”. Some of the work described at the festival may have been described in a related paper in the journal Cancer Research in 2010, entitled “Development of a novel tumour-targeted vascular disrupting agent activated by MT-MMPs”. This study focused on the effects of a derivative of colchicine, which the researchers called ICT2588, on one type of tumour in mice (fibrosarcoma).

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SWISS STUDY FINDS, DRUG REDUCES LUNG CANCER DEATHS :

Tamoxifen, which cancels out the sex hormone oestrogen, was first used to fight breast cancer more than 40 years ago. Some studies have shown that increasing levels of oestrogen, through hormone replacement therapy, increase the risk of lung cancer. The researchers at the University of Geneva asked if increasing oestrogen increased cancer deaths, would reducing oestrogen have the opposite effect. They analysed data on 6,655 women diagnosed with breast cancer between 1980 and 2003. Just under half had been prescribed anti-oestrogens. There was no significant difference in the number of women developing lung cancer, but those on anti-oestrogens did have a lower death rate. Evidence from large-scale clinical trials is needed before we know if these drugs could also be used as new treatments for people with lung cancer.

GLOWING DIE/FLUROSCENT DIE ‘BOOSTS’ CANCER SURGERY: Fluorescent tagging of ovarian cancer cells during diagnostic keyhole surgery is not only possible, but it can also help surgeons identify small areas of cancerous tissue that they cannot see by regular visual inspection alone. This potentially allows surgeons to better identify cancerous tissue when assessing the stage of the cancer by laparoscopy, a technique which is often used alongside other diagnostic imaging procedures such as CT and MRI scanning. It may also help surgeons ensure that they remove all cancerous tissue during therapeutic surgery, which will usually be quite a major operation. In particular, the authors consider that it may guide surgeons when performing debulking surgery, and so improve the likely efficiency of the chemotherapy that follows this.

MICROTUBULES AS A TARGET FOR ANTICANCER DRUGS:

Fig:  Microtubules in two human osteosarcoma cells in interphase of the cell cycle. Microtubules are in red, chromatin is in blue, and centromeres are in green. Image Microtubules are highly dynamic cytoskeletal fibres that are composed of tubulin subunits.

Microtubules are highly dynamic cytoskeletal fibres that are composed of tubulin subunits. They show two types of non-equilibrium dynamics — treadmilling and dynamic instability — both of which are crucial to mitosis and cell division. Dynamic microtubules continue to be one of the most successful cancer chemotherapeutic targets.Many new drugs that target microtubules are in clinical trials and large numbers of microtubule-active compounds are being developed. Among the most successful microtubule-targeted chemotherapeutic drugs are paclitaxel and the Vinca alkaloids,which were previously thought to work through opposite mechanisms.We now recognize that their most potent actions are suppression of microtubule dynamics, rather than increasing or decreasing microtubule-polymer mass. Microtubule-active drugs generally bind to one of three main classes of sites on tubulin, the paclitaxel site, the Vinca domain and the colchicine domain.Drugs that bind to the colchicine domain are undergoing intensive investigation as vasculartargeting agents for cancer therapy. Development of resistance to microtubule-targeted drugs has several possible causes, some of which might involve changes inmicrotubule dynamics resulting from altered expression of tubulin isotypes, tubulin mutations, and alteredexpression or binding of microtubule-regulatory proteins.  Microtubule-targeted drugs can synergize with one another. With purified microtubules in vitro (generally purified from pig, cow or sheep brains, which are a rich source of microtubules), dynamic instability of individual microtubules is measured by computer-enhanced time-lapse differential interference-contrast microscopy. In living cells, individual fluorescent microtubules can be readily visualized in the thin peripheral regions of the cells after microinjection of fluorescent tubulin or by expression of GFP (green fluorescent protein)-labelled tubulin. The growing and shortening dynamics of the microtubules,which are prominent in this region of interphase cells, are recorded by time-lapse using a sensitive CCD (charge-coupled device) camera.To determine how microtubule length changes with time, both in vitroand in living cells, the ends of the individual growing and shortening microtubules are traced by a cursor on succeeding time-lapse frames, recorded, and their rates, lengths and durations of growing and shortening are calculated from the sequence of recorded xy positions of the microtubule ends.

CAMPTOTHECIN DELIVERY USING NANOPARTICLE SYSTEMS
Nanoparticles are defined as the particles having its diameter in nanometer range. Nanoparticles are functional materials that can undergo surface modification for targeting cancer cells of cellular membrane, cytoplasmic or nuclei. Further-more, the encapsulation of anti-cancer drugs in the nano-particles can prevent the multi-drug resistance and prolong the circulation half life of drugs in the bloodstream. The nanoparticles consist of dendrimers, polymeric micelles, nanospheres, nanocapsules, fullerenes, nanotubes, and liposome, and can be different in material composition, drug loading capacity, drug stability, drug release rate, and target ability. Among these characteristic properties, the drug-carrying particles having defined particle diameter have been proven to preferentially accumulate in tumor mass because of the leaky vasculature of tumors which are socalled enhanced permeability and retention effect. IT-101 is a nanoparticle conjugated with CPT and a cyclodextrin based polymer. CPT was conjugated to the cyclodextrin at the 20-OH position which prevents the ring open of the lactone linkage of CPT. The molecular weight of polymers used was 35kDa or 97 kDa and CPT was linked to the cyclodextrin with the peptide spacer of triglycine. The mean particle size of IT-101 was in the range of 54nm to 78nm depending upon the CPT loading. In their report, CPT loading contents were 5.03 wt% and 7.36 wt%. The stability study showed no carboxylate form detected throughout a period of 7 hr. Time for one half CPT released from IT-101 at 37oC was dramatically decreased from 59 hr in PBS to 1.7 hr in human plasma. This result inferred that the plasma proteins can de-stabilize the IT-101 and resulted in higher release rate. In the pharmacokinetical study of the camptothecin-polymer conjugate (IT-101) in rats, after intravenous injection, plasma concentration of CPT released from IT-101 is 100-fold higher than that of free CPT. Moreover, IT-101 presented greater CPT concentration in tumor site than that of free CPT or irinotecan. Anti-tumor activity of IT-101 in human LS174T colon tumor-bearing nude mice showed that the maximum tolerated dose (MTD) of IT-101 is 9mg/kg and significant anti-tumor activities were observed as well when compared to the administration of free CPT.

CONCLUSION:
It is apparent that at present, drug-based therapeutic strategies will predominate in the 21st century. Thus, the discovery of new drugs effective against resistant tumors is an important and necessary strategy in improving chemotherapy. Natural drugs have found direct medical application as drug entities, but they also serve as chemical models or templates for the design, synthesis, and semisynthesis of novel substances, such as paclitaxel (Taxol), vincristine (Oncovin) and camptothecin, in the treatment of human cancer (Figure 1). Although there are some new approaches to drug discovery, such as a combination of chemistry and computer-based molecular modeling design, none of them can replace the important role of natural products in drug discovery and development.

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