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Natural product inhibitors of ovarian neoplasia. (Review).

Summary

The present work constitutes a review of the literature on natural products with potential antitumor activity against ovarian neoplasias. The review refers to five plant extracts and sixty-nine compounds isolated from higher plants and microorganisms, which are classified in appropriate chemical groups and model tested, and cites their activity. Some aspects of recent research with natural products directed to ward producing drugs which are inhibitors of ovarian neoplasia are discussed.

Key words: Ovarian, Neoplasia, Chemotherapy, Anticancer agent, Antitumor activity, Natural products, Medicinal plants

Introduction

The life expectancy of patients with malignant neoplasias has increased in recent years, because of early diagnosis and improvements in chemotherapy. Other primary tumors have frequently been diagnosed in the same individual (Fishman, 1998). A trend toward definitive associations of multiple primary tumors has been observed. In women, neoplasias of breast and ovary are most frequently related (Curtin et al., 1994).

The structure and function of the ovaries varies with the age of the individual, being strongest prominent during child-bearing years and atrophying after menopause. The ovaries are two small almond-shaped bodies, dull white in color, measuring approximately 2 cm in length, 1.5 cm in breadth and 1 cm in thickness. They are situated on either side of the pelvis, attached to the posterior layer of the broad ligaments and lying inside the peritoneal cavity below the bifurcation of the common iliac artery, anterior to the sacroiliac joints. The attachment of the ovary to the posterior layer of the broad ligament is known as the mesovarium. The ovary is suspended from the uterine cornu by the ovarian ligament, which runs inside the broad ligament to the mesovarium. The lateral pole of the ovary is supported by the infundibulo-pelvic ligament, which runs to the sidewall of the pelvis (Lambert and Soutter, 1990).

In the course of our continuing search for bioactive natural products from plants and microorganisms used as anticancer agents, we recently published two reviews on crude plant extracts and chemically defined molecules with potential antitumor activity against mammary (Moura et al., 2001) and uterine cervical neoplasia (Moura et al., 2002). In the present work we have reviewed the literature related with natural products which specifically inhibit ovarian neoplasias.

Materials and methods

The keywords used for this review were medicinal plants, natural products, ovarian, tumor and chemotherapy. The search perfound using Chemical Abstracts, Biological Abstracts and the data bank of The University of illinois at Chicago, NAPRALERT (Acronym for NAtural PRoducts ALERT), updated to April 2001. The references obtained were later consulted.

Results and Discussion

Plants have been used as sources of medicinal agents for milennia. As the age of modem, scientific medicine and single pure drugs has evolved, plant-derived active principles and their semi-synthetic and synthetic analogs have served as a major spurce for new pharmaceuticals for treatment of malignant tumors, including ovarian neoplasia.

The peak incidence of ovarian cancer occurs in women between 50 and 60 years of age. The treatment includes the following modalities: surgery, radiotherapy, and chemotherapy. Because many patients have stage III and IV disease upon presentation, chemotherapy has assumed an increasingly important role in management.

Consultation of various types of literature sources resulted in the elaboration of a list of natural products evaluated specifically for ovarian neoplasias. It should be noted that most of the references cited are not firsthand observations, but secondary sources. For details on the models or mechanism-based bioassays utilized for selecting plant extracts and pure compounds against ovarian tumors, the original references should be consulted.

Plant extract inhibitors of ovarian neoplasia

Although plants have a long history of use in the treatment of cancer, many, if not all, of the claims for the efficacy of such treatments should be viewed with some skepticism because ovarian neoplasia, as a specific disease entity, is poorly defined in folkloric and traditional medicine. In fact, in our search of the literature we found only five plant extracts with indications for neoplasias of ovaries, namely:

* Hymenocardia acida, Mangifera indica and Sida rhombifolia: The evaluation of the anticancer activity of extracts from these three medicinal plants collected in Zaire was carried out using the U.S. National Cancer Institute panel of human tumor cell lines provided for the preliminary screening of natural products. Methanol extracts from the root bark of H. acida, the stem bark of M. indica and the leaves of S. rhombifolia exhibited in-vitro cytotoxic activity against 6 human cell lines tested. Of these, the methanol extracts of H. acida and M. indica are suitable candidates for bioactivity-directed fractionation to isolate the chemical constituents responsible for the observed antitumor effects (Table 1) (Muanza et al., 1995). These tumor systems are acceptable models for the corresponding human disease.

* Cinnamomum cassia: The aqueous extract of C. cassia is used traditionally in China, South Korea and Marroco for amenorrhea (Hu, 1982; Lee et al., 1977; Bellakhdar et al., 1991), and also in China to prevent postpartum blood clotting, but the effects described refer to a multi-component preparation (Sun, 1964). In India, C. cassia is used as an abortifacient (Saha et al., 1961). Scientific studies in China report that the aqueous extract showed antitumor activity in treating 10 cases of liver and ovarian cancer and leukemia (Hu, 1982).

* Viscum album: The use of V album (mistletoe, European parasite) as a medicine for circulatory and nervous disorders dates from antiquity. The herb contains choline and acetylcholine-tyramine substances which are known for their regulatory effect on blood pressure and circulation, and for toning the heart muscle (ZeeCheng, 1997).

Since the 1920s, extracts from V album have been popular in Europe as an unconventional approach for cancer treatment. Starke 60 is an aqueous extract isolated from fresh mistletoe, although reports of its preparation have not been published. One ampoule of 1 ml contains 60 mg of the mistletoe extract, mainly as cancerostatic protein. The compound was marketed by Novipharm GmbH as Isorel[R] in Austria in 1983 and as Vysorel(r) in Germany in 1986 (Zee-Cheng, 1997). Results of studies with ovarian cancers, advanced breast and other tumors treated with V album are summarized in Table 2. In general, results show improvements in DNA repair in lymphocytes, cell-mediated immunity and modest survival rates.

Chemically-defined molecule inhibitors of ovarian neoplasia

We encountered 69 chemically defined molecules obtained from natural sources reported in the literature as useful for treatment of ovarian neoplasia. Of these, 52 compounds are in pre-clinical studies and 17 are currently used clinically in the chemotherapeutic treatment of the disease.

Some of the compounds evaluated, listed in Table 4, could serve as new leads for antineoplasic agents in the future. Three heterocyclic compounds, mycalamide-A and -B and onnamide, were isolated from Mycale sp. and Theonella sp. sponges collected in New Zealand and Okinawan waters. Only mycalamide-A and -B were active against M5076 ovarian sarcoma. Mechanism of action studies indicate that the compounds inhibited protein synthesis (Burres and Clement, 1989). The antitumor activity of FR901228, a non-alkaloid N-heterocycle compound isolated from Chromobacterium violaceum, prolonged the life of mice, inhibiting the growth of murine solid tumor M5076 reticulum cell sarcoma. FR901228 was also more effective against mitomycin C-, cyclophosphamide-, vincristine- and 5-fluorouracil-resistant P388 leukemias than against non-resistant P388 in mice. These results suggest that FR901228 will be a new type of drug for the treatment of cancer (Ueda et al., 1994). The bulbs of Pancratium littorale collected in Hawaii were f ound to contain a new phenanthridone alkaloid designated pancratistatin that proved to be effective (53-84% life extension at 0.38-3.0 mg/kg dose levels) against in vivo murine M5076 ovarian sarcoma (Pettit et al., 1986). The results of the literature survey are presented in Table 3. The compounds are arranged in alphabetical order, with each entry giving the following information in sequence: chemical name, class, organism tested, model, result and references.

Ten plant-derived compounds have been approved for use as clinical anticancer drugs in different types of ovarian neoplasias: etoposide, irinotecan, mitoxantrone, taxol, taxotere, teniposide, topotecan, vinblastine, vincristine and vinorelbine. Another seven agents [actinomycin-D, adriamycin, bleomycin, daunorubicin, epirubicin, mitomycin C and peplomycin] are microorganism-derived compounds (Table 4). It has been shown that a combination of synthetic agents and drugs of natural origin appears to be more effective than single-agent therapy, which was the previously-accepted standard (Baker, 1981). For example, platinum drugs are standard in the treatment of patients with ovarian cancer but carboplatin-paclitaxel has recently become the standard chemotherapy regimen for patients with advanced ovarian cancer or recurrent ovarian cancer (De Furia, 1997; Pujade et al., 2000). Primary choriocarcinoma of the ovary (PCO) is rare; this can be gestational (GCO) or nongestational (NGCO) in origin. It is difficult to di fferentiate between CGO and NGCO, but NGCO has a worse prognosis than GCO. Two cases of metastatic GCO were treated successfully with combination chemotherapy (Cyclophosphamide-methotrexate as synthetic agents and actinomycin D-bleomycin-etoposide-vincristine as natural drugs) and the patients were alive and disease free at the time of the report (Gangadharan et al., 1999). Topotecan is an active drug in platinum-sensitive epithelial ovarian carcinoma, with significant but manageable hematologic toxicity (McGuire et al., 2000). Angiosarcomas rarely involve the female genital tract. There have only been sporadic case reports of angiosarcomas of the cervix, uterus, vagina, parametrium, broad ligament and pelvis, and only 1 well-documented case of primary ovarian angiosarcoma in the literature to date. A case of primary pure ovarian angiosarcoma that had partial response after chemotherapy with adriamycin and ifosfamide was reported (Twu et al., 1999). Small cell carcinoma of the ovary (SCCO) is a highly aggress ive malignancy which affects young females. The disease is fatal in nearly all patients with disease categorized as higher than stage IA. A 30-year-old woman was diagnosed, while pregnant, as having bilateral small cell carcinoma, pulmonary type, a rare finding. She received three courses of JP chemotherapy (carboplatina, 525 mg; cisplatina, 120 mg) and three courses of PVP chemotherapy (peplomycin, 30 mg; vin-blastin 12 mg; cisplatin, 120 mg). Computer tomography scans were taken during and after the period in which she received chemotherapy. These showed growing multiple metastatic tumors and massive ascites. Third-line chemotherapy with paclitaxel (225 mg) was then initiated. Although the lymphadenopathy and massive ascites were alleviated, bone marrow suppression intervened. The patient died 18 months after diagnosing (Kawasaki et al., 2000).

The results of the literature survey are presented in Table 4. The compounds are arranged in alphabetical order, each entry giving the following information: chemical name, trademark (listing of trademarks is for information purposes only and it should not be assumed that the trademarks are in current use), class, source and references. The chemical structure of compounds is shown in Fig. 1.

Of the 69 compounds which have been isolated and identified (Table 3 and 4) and are available for ovarian neoplasias, 25 are alkaloids, 8 non-alkaloid N-heterocycles, 7 miscellaneous lactones, 4 proteids, 4 diterpenes, 4 anthraquinones, 3 peptides, 2 quinoids, 2 triterpenes, 2 sesquiterpenes, 2 flavonoids, 2 lignans, 1 carbohydrate, 1 carotenoid, I anthracene and 1 benzenoid. This study has revealed that the most promising leads are alkaloids (Table 5).

Conclusion

Of all the gynecologic cancers, ovarian malignancies represent the greatest clinical challenge because early diagnosis is difficult. Ovarian cancer is one of the classic hidden malignancies in the abdomen. When a patient finally presents symptoms, the volume of the tumor is usually very high and most of the time metastasis had already occurred. In order to improve the survival rate for ovarian cancer, research effort needs to be directed towards early diagnosis and more effective drug therapy.

We can conclude that in spite of the large incidence of ovarian neoplasia, attacks women all over the world, there is little in the literature about the use of products of natural origin that inhibit this pathology. Even so, there is a large variety of plants and microorganisms on our planet yet to be explored and, there is thus potential for reaching a stage in the future when an ovarian tumor will no longer be a threat.
Table 1

Cytoxicity profiles of methanol extracts from Himenocardia acida,
Mangifera indica and Sida rhombifolia against ovarian neoplasia.

Ovarian Growth percentage (*)
neoplasia
models H. acida M. indica S. rhombifolia

IGROV-1 73.6 56.4 -35.1
OVCAR-3 11.5 31.0 -43.5
OVCAR-4 41.9 45.0 -1.4
OVCAR-5 46.8 54.6 -46.1
OVCAR-8 >100.0 53.3 -44.1
SK-OV-3 -23.8 51.7 -12.1

* Figures are "% Growth" relative to concomitant and zerotime controls.

If >100, then Stimulative

if 0 to 100, then Cytostatic/ Cytotoxic

if Negative, then Cytolytic.

Table 2

Reported treatment of cancer patients with Viscum album extract.

Cancer Treatment and results Reference

Advanced * The depression of cell-mediated Coeugniet, 1987
ovarian immunity was determined in
cancer patients with ovarian carcinoma
 using lymphokine production
 by conc A stimulation,
 T-lymphocyte transformation
 test, and a skin reactivity
 test with V. album extract.
 * 20 women: Stage I and II 5-year Hassauer et
 survival, 100%, III, 23%, IV, 0%. al., 1979
 Postoperative treatment with
 V. album, III, 4.2 times longer,
 IV, 1.6 times longer. V. album
 extract is a useful treatment
 for ovarian carcinoma

Breast * Natural killer and antibody- Hajto and
cancer dependent cell-mediated Lanzrein, 1986
 cytotoxicity, as well as the
 number of stage granular
 lymphocytes, as improved.
 * Assays of cell-mediated Coeugniet, 1987
 immunity in patients showed
 good results with treatment.
 * Improvement of DNA repair in Kovacs et
 lymphocytes of breast cancer al., 1991
 patients with treatment: 12/14
 patients showed an improvement
 (2.7 times) due to stimulation
 of repair enzyme by lymphokine
 or cytokine.
 * Postoperation therapy (547 Leroi, 1977
 patients) after surgery of
 breast neoplasm.
 Stage I and II, 5 and 10-year
 survival rates are significantly
 improved with postoperative use
 of V. album. No toxic side-effects.

Various * Various tumor growths and Schultze et
tumors therapies are studied and compared. al., 1991

Table 3

Preclinical studies of chemically defined molecules as inhibitors of
ovarian neoplasia model.

 Organism
Chemical name Class tested Model

Abrin Proteid Human and Ca-Ovarian
 mouse
Acivicin Alkaloid Mouse Ca-Ovarian M5076
Aclacinomycin A Quinoid Human Ca-Ovarian
Actinomycin, [beta]-Pip Non-alkaloid Mouse Ca-Ovarian M5076
 N-heterocycle
Aphidicolin Diterpene Mouse Ca-Ovarian M5/DDP
Baccharin Sesquiterpene Mouse Ca-Ovarian M5076

Bryostatin 1 Miscellaneous Human and Ca-Ovarian M5076
 lactone mouse
Bullatacin Miscellaneous Mouse Ca-Ovarian A2780
 lactone
Bullatacinone Miscellaneous Mouse Ca-Ovarian A2780
 lactone
Colchicine Alkaloid Mouse Ca-Ovarian M5076
Dehydrodidemnin B Peptide Human Ca-Ovarian M5076
Didemnin B Peptide Human Ca-Ovarian M5076
Dolastatin 10 Proteid Mouse Ca-Ovarian OVCAR-3
Echinomycin Non-alkaloid Human Ca-Ovarian
 N-heterocycle
Ecteinascidin 722 Non-alkaloid Mouse Ca-Ovarian M5076
 N-heterocycle
Ecteinascidin 729 Non-alkaloid Mouse Ca-Ovarian M5076
 N-heterocycle
Ecteinascidin 743 Alkaloid Mouse Ca-Ovarian HOC22

Elactocin Miscellaneous Mouse Ca-Ovarian M5076
 lactone
Flavone acetic acid Flavonoid Mouse Ca-Ovarian IGROV-1
FR901228 Peptide Mouse Ca-Ovarian M5076
Ginsenoside RH-2 Triterpene Mouse Ca-Ovarian HRA

Gossypol Sesquiterpene Human Ca-Ovarian OVCAR-3
Homoharringtonine Alkaloid Human and Ca-Ovarian
 mouse
Hydroquinone Benzenoid Mouse Ca-Ovarian M5076
Indeno alkaloid Alkaloid Mouse Ca-Ovarian M5076

Kazusamycin A Miscellaneous Mouse Ca-Ovarian M5076
 lactone
Leurocristine Alkaloid Mouse Ca-Ovarian OVCAR-3
Radisky et al., 1993
Lycobetaine Alkaloid Human Ca-Ovarian
Lycopene Carotenoid Mouse Ca-Ovarian OVCAR-3

Makaluvamine A Alkaloid Mouse Ca-Ovarian OVCAR-3
Makaluvamine B Alkaloid Mouse Ca-Ovarian OVCAR-3
Makaluvamine C Alkaloid Mouse Ca-Ovarian OVCAR-3
Maytansine Non-alkaloid Human Ca-Ovarian
 N-heterocycle
Methylnogarol Quinoid Mouse Ca-Ovarian M5076

Mycalamide A Alkaloid Mouse Ca-Ovarian MS 076

Mycalamide B Alkaloid Mouse Ca-Ovarian M5076

Nitidine Alkaloid Mouse Ca-Ovarian M5076

Onnamide Alkaloid Mouse Ca-Ovarian M5076

Pancratistatin Alkaloid Mouse Ca-Ovarian M5076
Polysacch. DS-4152 Carbohydrate Mouse Ca-Ovarian M5076
Pseudolaric acid B Diterpene Mouse Ca-Ovarian A2780

Quercetin Flavonoid Human Ca-Ovarian
Quinocarmycin Alkaloid Mouse Ca-Ovarian M5076
Rhizoxin Miscellaneous Human Ca-Ovarian
 lactone
Ricin Proteid Mouse Ca-Ovarian

Rolliniastatin 2 Miscellaneous Mouse Ca-Ovarian A2780
 lactone
Thiocolchicine Alkaloid Mouse Ca-Ovarian M5076
Trimethyl- Alkaloid Human Ca-Ovarian
 colchicinic acid
Vincaleukoblastine Alkaloid Human Ca-Ovarian
Viscum peptide Proteid Mouse Ca-Ovarian M5076
Vismione A Anthracene Mouse Ca-Ovarian M5076
Wortmannin Triterpene Mouse Ca-Ovarian M5076


Chemical name Result Reference

Abrin Active Tung et al, 1975;
 Fodstad et al., 1977
Acivicin Active Bogden et al., 1979
Aclacinomycin A Active Lev and Posada, 1983
Actinomycin, [beta]-Pip Inactive Parker et al., 1983

Aphidicolin Active Damia et al., 1992
Baccharin Active Douros and Suffness,
 1981
Bryostatin 1 Active Jayson et al., 1995;
 Hornung et al., 1992
Bullatacin Active Kinghorn and
 Balandrin, 1993
Bullatacinone Active Ahammadasahib
 et al., 1993
Colchicine Active Kerekes et al., 1985
Dehydrodidemnin B Active Rinehart, 2000
Didemnin B Inactive Malfetano et al., 1993
Dolastatin 10 Active Pettit et al., 1993
Echinomycin Active Muss et al., 1990

Ecteinascidin 722 Active Rinehart and Sakai,
 1995
Ecteinascidin 729 Active Rinehart and Sakai,
 1995
Ecteinascidin 743 Active Rinehart, 2000;
 Jimenoetal., 1996
Elactocin Active Pettit et al., 1994

Flavone acetic acid Active Pratesi et al., 1991
FR901228 Active Ueda, 1994
Ginsenoside RH-2 Active Tode et al., 1993;
 Nakata et al., 1998
Gossypol Active Bens et al., 1990
Homoharringtonine Inactive Kavanagh et al., 1984

Hydroquinone Inactive Arisawa et al., 1984
Indeno alkaloid Active Cushman and Mohan,
 1985
Kazusamycin A Active Pettit, 1994

Leurocristine Inactive Mattem et al., 1984;
Radisky et al., 1993
Lycobetaine Active Hsu, 1980; Hsu, 1981
Lycopene Active Levi and Sharoni,
 1994
Makaluvamine A Active Radisky et al., 1993
Makaluvamine B Inactiva Radisky et al., 1993
Makaluvamine C Active Radisky et al., 1993
Maytansine Active Chabner et al., 1978

Methylnogarol Active Douros and Suffness,
 1981
Mycalamide A Active Burres and Clement,
 1989
Mycalamide B Active Burres and Clement,
 1989
Nitidine Inactive Cushman and Mohan,
 1985
Onnamide Inactive Burres and Clement,
 1989
Pancratistatin Active Pettit et al., 1986
Polysacch. DS-4152 Active Tanaka et al., 1989
Pseudolaric acid B Active Kinghom and
 Balandrin, 1993
Quercetin Active Ferry et al., 1996
Quinocarmycin Active Fujimoto et al., 1987
Rhizoxin Inactive Kerr et al., 1995

Ricin Active Pihi et al., 1980; Pihl
 and Fodstad, 1983
Rolliniastatin 2 Active Ahammadasahib
 et al., 1993
Thiocolchicine Active Kerekes et al., 1985
Trimethyl- Active Ru et al., 1990
 colchicinic acid
Vincaleukoblastine Active Young et al., 1985
Viscum peptide Active Cassinelli et al., 1986
Vismione A Active Cassinelli et al., 1986
Wortmannin Active Schultze et al., 1995

Table 4

Clinical use of chemically defined molecules a inhibitors of ovarian
neoplasia.

Chemical name Trademarker Class Source

Actinomycin-D Dactinomycin Non-alkaloid Streptomyces spp.
 N-heterocycle


Adriamycin Doxorubicin Anthraquinone Streptomyces peucetius



Bleomycin Blenoxane Non-alkaloid Streptomyces verticillus
 N-heterocycle






Daunorubicin Daunoblastina Anthraquinone Streptomyces peucetius

Epirubicin Farmorubicin Anthraquinone Analog of adriamycin D

Etoposide VP-16 Lignan Prepared from
 podophyllotoxin (1)



Irinotecan Camptosar, Alkaloid Prepared from
 CPT-11 camptothecin (2)

Mitomycin C Mutamycin Alkaloid Streptomyces caespitosus

Mitoxantrone Novantrone Anthraquinone Prepared from
 anthraquinone nucleus
Peplomycin Peplo Injection Non-alkaloid Derivative of bleomycin
 N-heterocycle
Taxol Paclitaxel Diterpene Taxus brevifolia



Taxotere Docetaxel Diterpene Derivative of taxol

Teniposide VM-26 Lignan Prepared from
 podophyllotoxin (1)
Topotecan Hycamtin Alkaloid Prepared from
 camptothecin (2)
Vinblastine Velban Alkaloid Vinca rosea


Vincristine Oncovin Alkaloid Vinca rosea





Vinorelbine Navelvine Alkaloid Derivative of vinblastine



Chemical name Clinical use

Actinomycin-D * Coriocarcinoma of the ovary
 * Non-seminomatous tumor of the
 ovary
 * Ovarian germ-cell malignancy
Adriamycin * Advanced ovarian cancer
 * Angiosarcoma of ovary

 * Clear-cell carcinoma of the ovary
Bleomycin * Coriocarcinoma of the ovary
 * Ovarian germ-cell malignancy
 * Non-seminomatous tumor of the
 ovary
 * Granulose cell tumors of the
 ovary
 * Ovarian dysgerminoma
 * Yolk sac tumor of the ovary
Daunorubicin * Advanced ovarian cancer
 * Granulocytic sarcoma of the ovary
Epirubicin * Advanced ovarian cancer

Etoposide * Advanced ovarian cancer
 * Coriocarcinoma of the ovary
 * Non-seminomatous tumor of the
 ovary
 * Ovarian dysgerminoma
Irinotecan * Advanced ovarian cancer
 * Cystadenocarcinoma of the ovary
 * Clear-cell carcinoma of the ovary
Mitomycin C * Cystadenocarcinoma of the ovary
 * Clear cell carcinoma of the ovary
Mitoxantrone * Advanced ovarian cancer

Peplomycin * Small cell carcinoma of the ovary
 * Malignant ovarian tumors
Taxol * Small cell carcinoma of the ovary
 * Clear cell carcinoma of the ovary
 * Advanced ovarian cancer
 * Mullerian tumor of the ovary
Taxotere * Advanced ovarian cancer

Teniposide * Malignant ovarian tumors

Topotecan * Advanced ovarian cancer

Vinblastine * Small cell carcinoma of the ovary
 * Yolk sac tumor of the ovary
 * Malignant ovarian tumors
Vincristine * Coriocarcinoma of the ovary
 * Granulose-theca tumors of the
 ovary
 * Malignant ovarian tumors
 * Non-seminomatous tumor of the
 ovary
Vinorelbine * Advanced ovarian cancer



Chemical name Reference

Actinomycin-D Gangadharan et al., 1999
 Baranzelli et al., 2000

 Sumi et al., 2000
Adriamycin Yokoynma et al., 2000
 Di-Leo, 1999
 Platt et al., 1999
 Kita et al., 2000
Bleomycin Gangadharan et al., 1999
 Sumi et al., 2000
 Baranzelli et al., 2000

 Peeorelli et al., 1999

 Brewer et al., 1999
 Kawai et al., 1999
Daunorubicin Yokoyama et al., 2000
 Sreejith et al., 2000
Epirubicin Papadimitriou et al., 2000
 Pfisterer, 2000
Etoposide Li et al., 2000
 Gangadharan et al., 1999
 Baranzelli et al., 2000

 Brewer et al., 1999
Irinotecan Koshiyama et al., 2000
 Takizawa et al., 1997
 Shimizu et al., 1998
Mitomycin C Takizawa et al., 1997
 Umezawa et al., 1996
Mitoxantrone Topuz et al., 1998
 Le-Donne et al., 1997
Peplomycin Kawasaki et al., 2000
 Koyama et al., 1998
Taxol Kawasaki et al., 2000
 Patsner, 1998
 Schink et al., 2001
 Eltabbakh and yadav, 1999
Taxotere Markman et al., 2000
 Vasey et al., 1999
Teniposide Cheng et al., 1999

Topotecan Bookman et al., 1998
 Cacciari et al., 2000
Vinblastine Kawasaki et alk., 2000
 Kawai et al., 1999
 Herrmann, 1997
Vincristine Gangadharan et al., 1999
 Peeorelli et al., 1999

 Cesano et al., 1999
 Baranzelli et al., 2000

Vinorelbine Gershenson et a., 1998
 Burger et al., 1999
 Cicchetti et al., 2000

(1) Podophyllotoxin is a lignan isolated from Podophyllum peltatum

(2) Camptothecin is an alkaloid isolated from Camptotheca acuminata

Table 5

Rank of natural products that present activity in ovarian neoplasias.

Class Rank %

Alkaloids 37
Non-alkaloid N-heterocycles 13
Miscelaneous lactone 11
Diterpenes 6
Proteids 6
Anthraquinones 4
Peptides 4
Flavonoids 3
Lignans 3
Quinoids 3
Sesquiterpenes 3
Triterpenes 3
Anthracenes 1
Benzenoids 1
Carbohydrates 1
Carotenoids 1


Acknowledgments

The authors wish to express their sincere thanks to the College of Pharmacy, The University of Illinois at Chicago, Chicago, Illinois 60612-7231, U.S.A., for helping with the computer-aided NAPRALERT search.

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Author:Silva, J.S.; Moura, M.D.; Oliveira, R.A.G.; Diniz, M.F.F.; Barbosa-Filho, J.M.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:1USA
Date:Mar 1, 2003
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