SYNTHETIC ANTICANCER DRUGS USEFUL AGAINST OVARIAN CANCER

Submitted by: Faiz Miran Submitted to:

AN OVERVIEW
Ovarian cancer, a condition characterized by an overgrowth of malignant cells in one or both of the ovaries, is one of the deadliest and under-recognized cancers affecting women. Ovarian cancer is diagnosed in nearly a quarter of a million women globally each year. It is the eighth most common cancer in women and the seventh leading cause of cancer death among women, responsible for approximately 140,000 deaths each year. It has the highest mortality rate of all gynecological cancers. The prognosis for ovarian cancer patients is poor, particularly when the disease is diagnosed in its later stages. Symptoms are ambiguous and often misdiagnosed, so the majority of patients are only identified in the advanced stages of the disease. Ovarian cancer is therefore often referred to as The Silent Killer. The current standard of care for ovarian cancer - surgery and chemotherapy has remained unchanged for many years and the 5-year survival rate has improved by only 9% since 1975. Statistics show that just 45% of women with ovarian cancer are likely to survive for five years compared to up to 89% of women with breast cancer. This outcome is due, in large part, to the lack of effective prevention and early detection strategies; when diagnosed at an early stage, the survival rate is approximately 95% with current treatment modalities. Thus, prevention and early detection of this disease would be of clear clinical benet

OVARIAN CANCER TREATMENT

When symptoms finally show up and the doctor suspects that a patient may have ovarian cancer, laparoscopy is conducted to confirm diagnosis. It is a direct visual examination of the abdominal cavity, the ovaries, the exterior of the fallopian tubes and the uterus using an instrument that is inserted just underneath the navel. Upon confirmation of ovarian cancer, the doctor explores the extent of the cancer and submits the patient for surgery. The surgeon removes the growth or
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much of the malignant tissue. In most cases, the whole ovary or both of the ovaries and the fallopian tubes are removed as they the malignant cancer cells have already affected these areas. This kind of surgery is called salpingooophorectomy. If the malignant cells affect the uterus, hysterectomy is conducted (surgical removal of the uterus). Surgery is usually ensued by radiotherapy, which is the use of high energy radiation to destroy malignant cancer cells in the body and shrink remaining tumors, which may later on become malignant. This procedure may be done using an external machine or a radioactive material put inside the body near the malignant cells. The patient also undergoes chemotherapy, whereby the patient is given anti-cancer drugs to help hasten up ovarian cancer treatment. Drugs may be administered orally (through the mouth), intravenously (through the veins) or through the muscles (by means of injection of a needle. Most anticancer drugs given to the patient have chemical compounds that are toxic to the malignant cells; thus, growth of the cancer cells is reduced or stopped. These anticancer drugs are called cytotoxic drugs. Other anticancer drugs used are synthetic forms of sex hormones such as androgen drugs and progesterone drugs. In most instances, different kinds of anticancer drugs are prescribed in combination in order to speed up ovarian cancer treatment. However, not all ovarian cancer patients are given with the same anticancer drugs. The drugs given to a patient depends on the extent or stage of development of the ovarian cancer and her general health condition.

SYENTHETIC ANTICANCER DRUGS USES FOR OVARIAN CANCER

Around the world, tremendous resources are being invested in prevention, diagnosis, and treatment of ovarian cancer. Identification of cytotoxic compounds led the development of

ovarian anticancer therapeutics for several decades. Advances in cancer treatment, however, continued to be limited by the identification of unique biochemical aspects of malignancies that could be exploited to selectively target tumor cells. Schwartzman et al. noted in 1988 that of over 600,000 compounds screened by then, less than 40 agents were routinely used in the clinic. The recent growth in molecular sciences and the advances in genomics and proteomics have generated several potential new drug targets, leading to changes in the paradigms of anticancer drug discovery toward synthetic molecularly targeted therapeutics. These shifting paradigms have not only resulted in the greater involvement of biological scientists in the drug discovery process but also required changes in the screening and clinical evaluation of drug candidates. Both small and large synthetic molecular compounds continue to be investigated as anticancer agents. Although cytotoxic strategy has achieved significant success, the recent developments in molecular biology and an understanding of the pharmacology of cancer at a molecular level have challenged researchers to come up with target-based drugs. These are the agents that are predesigned to inhibit and/or modify a selected molecular marker deemed important in cancer prognosis, growth, and/ or metastasis. Several target-based synthetic compounds have emerged in recent years. Camptothecin, an alkaloid from the Chinese tree, Camptotheca acuminata Descne , was discovered by Wall and Wani. Although showing promising antitumor activity, clinical studies were discontinued due to unpredictable side effects. Subsequent semisynthetic modifications led to the development of Ironotecan (Topotecin, Campto), a derivative of camptothecin that is now clinically available. The camptothecins act by inhibition of the topoisomerase I.

O
N N O

HO

Camptothecin

N N N O N O O N

O
HO

Ironotecan Included among the most important anticancer drugs in use today are tamoxifen and methotrexate, which are both synthetic drugs for ovarian cancer. Tamoxifen was derived from the diethylstilbesterol nucleus, which itself was patterned after estradiol. First reported for its contraceptive activity in rats, tamoxifen was later found to bind to human estrogen receptors, thus paving the way for its use in the treatment of breast cancer. Tamoxifen is now one of the most widely used and successful drugs in the treatment of ovarian cancer. Methotrexate is an antifolate, patterned after physiological folate, is one of the most widely used antineoplastic drugs available, and shows efficacy in the treatment of a variety of neoplasms.

O H 3C

CH3

CH3

Tamoxifen

NH2 N N H2N N N

CH3 N

CONHCH(CO2H)CH2CH2CO2H

Methotrexate Although most of the drugs in use today are synthetic drugs, many (perhaps half or more) had their beginnings as natural products. Only a few have been cited here for illustrative purposes. Safety, efficacy, pharmacokinetics, metabolic or chemical stability, and other important characteristics of a drug are functions of the chemical structure of the molecule, not its origin. The molecular structure of a compound, which defines its interactions with other molecules in the body, is the prime reason it exhibits desirable and/or undesirable biological activities. Whether the compound is of natural or synthetic origin is irrelevant. To correlate origin with an expected greater or lesser safety profile or desirable features is unfounded, and can be dangerously misleading. Many of the most toxic chemical substances known are natural products, and some of the safest, most effective, and widely used drugs are of synthetic origin. In fact, structureactivity relationship (SAR) studies and synthetic modifications of bioactive
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natural products are usually done in an effort to produce an improved drug substance with a better therapeutic index. Thus, many of the most successful and important drug substances are derived through a combination of natural product chemistry and synthetic chemistry.