Abstract
Podophyllum hexandrum Royle of family Berberidaceae is an endangered medicinal plant. Rhizome ofP.hexandrum contains several lignans which posses antitumor activity. Podphyllotoxin is the most active cytotoxic natural product. It is used as starting compound for the synthesis of anticancer drug etoposide and teniposide. Podophyllotoxin acts as an inhibitor of microtubule assembly. These drugs are used for lung cancer, testicular cancer, neuroblastoma, hepatoma and other tumors. Besides this, it also shows antiviral activities by interfering with some critical viral processes. Availabilityof podophyllotoxin from plants has its limitations because of its intense collection from nature and lack of organized cultivation. The chemical synthesis of podophyllotoxin is considered to be very complicated as yet. The use of biotechnological approaches for the production of podophyllotoxin using cell cultures, organ cultures, and biotransformation route or by manipulating biosynthetic pathway proves to be an attractive alternative for production of podophyllotoxin. The present paper discusses the current status of research, limitations and future prospects for theproduction of podophyllotoxinin vitro.
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References
Aapro MS (1996) Oral etopoide and pallitative treatment for small cell lung cancer [Commentary]. Lancet 348: 559.
Arumugam N and Bhojwani SS (1990) Somatic embryogenesis in tissue cultures ofPodophyllum hexandrum. Can J Bot 68: 487–491.
Baker JT, Borris RP and Carte B et al. (1995) Natural product drug discovery and development: New perspectives on international collaboration. J Nat Prod 58: 1325–1327.
Berlin J, Bedorf N, Mollenschott C, Wray V, Sasse F and Hofle G (1988) On the podophyllotoxins of root cultures ofLinum flavum. Planta Med 54: 204–206.
Cai X, Woo MH, Edick MJ and Relling MV (1999) Simultaneous quantification of etoposide and its catechol metabolite in human plasma using high-performance liquid chromatography with electrochemical detection. J Chromatogr B Biomed Sci Appl 728: 241–250.
Clark PI and Slevin ML (1987) The clinical pharmacology of etoposide and teniposide. Clin Pharmacokin 12: 223–252.
Chabner BA, Allegra CJ and Curt GA et al. (1996) Antineoplastic agents. In: Hardman JG, Limbird LE and Molinoff PB et al. (eds) Goodman and Gilman's the Pharmacological Basis of Therapeutics. 9th ed. (pp 1233–1287) Mc Graw-Hill, New York.
Chabner BA and Myers CE (1989) Clinical pharmacology of cancer chemotherapy. In: De Vita VT, Hellman S and Rosenberg SA (eds) Cancer: Principles and Practice of Oncology, 3rd ed. JB Lippincott Co, Philadelphia.
Chang LW, Yang CM, Chen CF and Deng JF (1992) Experimental podophyllotoxin (bajiaolian) poisoning: I. Effects on the nervous system. Biomed Environ Sci 5: 283–292.
Charlton JL (1998) Antiviral activity of lignans. J Nat Prod 61: 1447–1451.
Cragg GM, Newman DJ and Snader KM (1997) Natural products in drug discovery and development. J Nat Prod 60: 52–60.
Damayanthi Y and Lown JW (1998) Podophyllotoxins: Current status and recent developments. Curr Med Chem 5: 205–252.
Dewick PM (1989) Tumour inhibitors from plants. In: Rahman AU (ed.) Studies in Natural Products Chemistry, Vol 5 (pp. 459–503) Elsevier, Amsterdam.
Dorr RT and Von Hoff (1994) Cancer Chemotherapy Handbook, 2nd ed. Norwalk: Appleton and Lange, 1994: 459–472.
Drew SE, Conway SJ, Jenning P and Helliwell K (1987) Determination of the aryltetralin lignan content of podophyllum resins and roots/rhizomes. J Pharm Pharmacol 39: 738–739.
Fay DA and Ziegler HW (1985) Botanical sources differentiation ofPodophyllum resin by high performance liquid chromatography. J Liq Chromatogr 8: 1501–1506.
Ferguson LR and Pearson A (1992) Chromosomal changes in Chinese hamster AAB cells caused by podophyllin, a common treatment for genital warts. Mutat Res 266: 231–239.
Filly CM, Grah-Radford NR, Lacy JR, Heitner MA, Earnest MP (1982) Neurologic manifestations of podophyllin toxicity. Neurology 32: 308–311.
Forsey SP, Rajapaksa D, Taylor NJ and Rodrigo R (1989) Comprehensive synthetic route to eight diastereomericPodophyllum lignans. J Org Chem 54: 4280–4290.
Franssen MCR and Walton MJ (1999) Biotransformations. In: Walton MJ and Brown DE (eds) Chemicals from Plants, Perspectives on Plant Secondary Products (pp. 277–325) Imperial College Press, London.
Giri A and Lakhmi Narasu M (1999) Transgenic hairy roots: Recent trends and applications. Biotechnology Advances (in press).
Goel HC, Prasad J, Sharma A and Singh B (1998) Antitumour and radioprotective action ofPodophyllum hexandrum. Indian J Exp Biol 36: 583–587.
Gowdey G, Lee RK and Carpenter WM (1995) Treatment of HIVrelated hairy leukoplakia with podophyllum resin 25% solution. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 79: 64–67.
Greenwald RB, Conover CD and Pendri A et al. (1999) Drug delivery of anticancer agents: Water soluble 4-poly ethylene glycol derivatives of the lignan, podophyllotoxin. J Controlled Release 61: 281–294.
Gupta R and Sethi KL (1983) Conservation of medicinal plant resources. In: Jain SK and Mehra KL (eds) Conservation of tropical plant resources (pp.101–107). Botanical Survey of India, Howrah.
Handa SS, Chawla AS and Maninder A (1989) Hypoglycemic plants: a review. Fitotherapia 60: 195.
Haskell CM, (1990) Cancer treatment, 3rd ed. WB Saunders Co, Philadelphia.
Heyenga AG, Lucas JA and Dewick PM (1990) Production of tumour-inhibitory lignans in callus cultures ofPodophyllum hexandrum. Plant Cell Rep 9: 101–116.
Holthuis JJM (1988) Etoposide and teniposide. Biosynthesis, metabolism and clinical pharmokinetics. Pharm Weekbl (Sci) 10: 101–116
Inamori Y, Kubo M, Tsujibo H, Ogawa M, Kozawa M and Fujita E (1986) The biological activities of podophyllotoxin compounds. Chem Pharm Bull 34: 3928–3932.
Jackson DE and Dewick PM (1984) Aryltetralin lignans fromPodophyllum hexandrum andPodophyllum peltatum. Phytochemistry 23: 1147–1152.
Kadkade PG (1981) Formation of podophyllotoxins byPodophyllum peltatum tissue cultures. Naturwissenschaften 68: 481–482.
Kadkade PG (1982) Growth and podophyllotoxin production in callus tissues ofPodophyllum peltatum. Plant Sci Lett 25: 107–115.
Kamil WM and Dewick PM (1986) Biosynthetic relationship of aryltetralin lactone lignans to dibenzylbutyrolactone lignans. Phytochemistry 25: 2093–2102.
Kao WF, Hung DZ, Tsai WJ, Lin KP and Deng JF (1992) Podophyllotoxin intoxication: toxic effects of Bajiaolian in herbal therapeutics. Hum Exp Toxicol 11: 480–487.
Kaplan IW (1942) Condyloma acuminata. New Orl Med Surg J 94: 388–395.
Krogh CME (1993) Compendium of pharmaceuticals and specialties, In: Krogh CME (ed) Canadian Pharmaceutical Association. Ottawa. Vol 28 (pp. 1307–1308).
Kutchan TM (1995) Alkaloid biosynthesis-The basis for metabolic engineering of medicinal plants. The Plant Cell 7: 1059–1070.
MacRae WD and Towers GHN (1984) Biological activities of lignans. Phytochemistry 23: 1207–1220.
Mayeaux EJ Jr, Harper MB, Barksdale W and Pope JB (1995) Noncervical human papillomavirus genital infections. Am Fam Physician 52: 1137–46, 1149–50.
Montaldo PG, Figoli F and Zanette MI et al. (1990) Pharmacokinetics of intrapleural versus intravenous etoposide (VP-16) and teniposide (VM-26) in patient with malignant pleural effusion. Oncology 47: 55–61.
Oostdam A, Mol JNM and Vanderplas LHW (1993) Establishment of hairy root cultures ofLinum flavum producing the lignan 5-methoxy podophyllotoxin. Plant Cell Reports 12: 474–477.
Purohit MC, Bahuguna R, Maithani UC, Purohit AN and Rawat MSM (1999) Variation in podophylloresin and podophyllotoxin contents in different populations ofPodophyllum hexandrum. Current Science 77: 1078–1080.
Przepiorka D, van Besien K and Khouri I et al. (1999) Carmustine, etoposide, cytarabine and melphalan as a preparative regimen for allogeneic transplantation for high-risk malignant lymphoma. Ann Oncol 10: 527–532.
Rassmann I, Thodtmann R and Mross M et al. (1999) Phase I clinical and pharmacokinetic trial of the podophyllotoxin derivative NK611 administered as intravenous short infusion. Invest New Drugs 16: 319–324.
Reiser M, Jostingg A and Draube A et al. (1999) Successful peripheral blood stem cell mobilization with etoposide (VP-16) in patients with relapsed or resistant lymphoma who failed cyclophosphamide mobilization. Bone Marrow Transplant 23: 1223–1228.
Richter A, Strausfeld U and Knippers R (1987) Effects of VM-26 (teniposide), a specific inhibitor of type Iitopoisomerase, on SV-40 DNA replicationin vivo. Nucleic Acid Res 15: 3455–3468.
Robles SJ, Buehler PW, Negrusz A and Adami GR (1999) Permanent cell cycle arrest in asynchronously proliferating normal human fibroblasts treated with doxorubicin or etoposide but not camptothecin. Biochem Pharmacol 58: 675–685.
Romanelli F (1996) Podophyllin. Clinical Toxicology Review 18: 1–5.
Rowinsky EK and Donehower (1992) Vinca alkaloids and epipodophyllotoxins. In: Perry MC (ed.) The Chemotherapy Source Book. (pp. 359–83, 640, 668) Williams and Wilkins, Baltimore.
Rust RW and Roth RR (1981) Seed production and seedling establishment in the Mayapple,Podophyllum peltatum L. Am Midl Natur 105: 51–60.
Santana VM, Schell MJ and Williams R et al. (1992) Escalating sequential high-dose carboplatin and etoposide with autologous marrow support in children with relapsed solid tumours. Bone Marrow Transplant 10: 457–462.
Schacter L (1996) Etoposide phosphate: what, why, where, and how? Semin Oncol 23: 1–7.
Stahelin HF and von Wartburg A (1989) From podophyllotoxin glucoside to etoposide. Prog Drug Res 33: 169–266.
Stahelin HF and von Wartburg A (1991) From the chemical and biological route from podophyllotoxin glucoside to etoposide, ninth Cain memorial award lecture. Cancer Res 51: 5–15.
Subrahmanyam D, Renuka B, Kumar GS, Vandana V and Deevi DS (1999) 9-Deoxopodophyllotoxin derivatives as anti-cancer agents. Bioorg Med Chem Lett 9: 2131–2134.
Thakur RS (1993) Plant drugs: Emerging areas of modern drug research. In: Govil JN, Singh VK and Hashmi S (eds) Glimpses in Plant Research Vol. XI (pp. 371–375) Today and Tomorrow's Publishers, New Delhi.
Truedsson L, Geborek P and Sturfelt G (1993) Antiproliferative effects on human peripheral blood mononuclear cells and inhibition of in vitro immunoglobulin synthesis by podophyllotoxin (CPH86) and by semisynthetic lignan glycosides (CPH82). Clip Exp Rheumatol 11: 179–82.
Ushio Y, Kochi M, Kuratsu J, Itoyama Y and Marubayashi T (1999) Preliminary observations for a new treatment in children with primary intracranial yolk sac tumour or embroynal carcinoma. Report of five cases. J Neurosurg 90: 133–137.
Van Uden W, Pras N, Visser JF and Malingre TM (1989) Detection and identification ofpodophyllotoxin produced by cell cultures derived fromPodophyllum hexandrum Royle. Plant Cell Reports 8: 165–168.
Van Uden W, Pras N and Malingre TM (1990) On the improvement of the podophyllotoxin production by phenylpropanoid precursor feeding to cell cultures ofPodophyllum hexandrum Royle. Plant Cell Tiss Org Cult 23: 217–224.
Van Uden W, Woerdenbag HJ and Pras N (1994) Cyclodextrins as a useful tool for bioconversions in plant cell biotechnology. Plant Cell Tiss Org Cult 38: 103–113.
Viana MB, Oliveira M and Silva CM et al. (1991) Etoposide in the treatment of six children with langerhans cell histiocytosis (histiocytosis X). Med Pediatr Oncol 19: 289–294.
Walter MH, Grima-Pettenati J, Grand C, Boudet AM and Lamb CJ (1988) Cinnamyl-alcohol dehydrogenase, a molecular marker specific for lignin synthesis: cDNA cloning and MRNA induction by fungal elicitor. Proc Natl Acad Sci USA 85: 5546–5550.
White DJ, Billingham C, Chapman S, Drake S, Jayaweera D, Jones S, Opaneye A and Temple C (1997) Podophyllin 0.5% or 2.0% v podophyllotoxin 0.5% for the self treatment of penile warts: a double blind randomized study. Genitourin Med 73: 184–187.
Winik NJ, McKenna RW and Shuster JJ et al. (1993) Secondary acute myeloid leukemia in children with lymphoblstic leukemia treated with etoposide. J Clin Oncol 11: 209–217.
Woerdenbag HJ, Van Uden W, Frijlink HW, Lerk CF, Pras N and Malingre TM (1990) Increased podophyllotoxin production inPodophyllum hexandrum cell suspension cultures after feeding coniferyl alcohol as aβ-cyclodextrin complex. Plant Cell Reports 9: 97–100.
Zhu XK, Guan J, Tachibana Y and Bastow KF et al. (1999) Antitumor agents. 194. Synthesis and biological evaluations of 4-beta-mono-, di-, and trisubstituted aniline-4'-O-demethylpodophyllotoxin and related compounds with improved pharmacological profiles. J Med Chem 42: 2441–2446.
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Giri, A., Lakshmi Narasu, M. Production of podophyllotoxin from Podophyllum hexandrum: a potential natural product for clinically useful anticancer drugs. Cytotechnology 34, 17–26 (2000). https://doi.org/10.1023/A:1008138230896
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DOI: https://doi.org/10.1023/A:1008138230896