Herb Drugs Of Taxol

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Taxol, a diterpene, is the latest antineoplastic drug of natural origin. Between 1960 and 1982, NCI evaluated 3500 plant samples primarily against mouse leukaemia cell lines L1210 and P388. Taxol was the outcome of that programme and got approval from the US Food and Drug Administration for the treatment of refractory ovarian cancer in 1992 and metastatic breast cancer in 1994 [77]. Taxol was first obtained from T. brevifolia (bark contains 0.01 to 0.03% taxol) during the 1960s and subsequently from bark of T. baccata and other Taxus spp. This long development time was due to the limited supply associated with killing of the plant upon removal of the bark. Paclitaxel and its derivatives act by binding tubulin without allowing depolymerisation or interfering with tubulin assembly [78, 79].

Bristol-Mayers Squibb, USA, is producing taxol (drug) at the commercial level. It is estimated that about 50 kg of taxol will be required every year for the treat-

Table 10.1 Antineoplastic natural compounds and their stages of clinical development

Action site

Drug derivatives

Disease type

Stage of clinical evaluation

Reference

A. Tubulin

Vinca domain

Vinblastine (Velban)

Hodgkin's disease, testicular germ cell cancer

In clinical use, 22 combination trials

[88]

Vincristine (Oncovin)

Leukaemia, lymphomas

In clinical use, 108 combination trials

[88]

Vinorelbine (Navelbine)

Solid tumours, lymphomas, lung cancer

In clinical use, 29 phase I—III trials (single or combination)

[88, 89]

Vinflunine

Bladder, breast cancer

phase III

[88,90,91]

Taxane site

Paclitaxel and analogues

Ovarian, breast and lung tumours, Kaposi's sarcoma, several other tumours

In clinical use, 207 phase I- II trials

[92]

Docetaxel (Taxotere)

Prostate, brain and lung tumours

Phase I—III trials

[93, 94]

Colchicine domain

Combretastatin AVE-8062

Potential vascular targeting compounds

Phase I-II

[95, 98]

B. Other (apoptosis, protein kinase

Homoharrintonine

Hematologic malignancies

Phase I

[99]

Ingenol-3-O-angelate Phenoxodiol

Skin cancer

Ovarian, prostate, renal, vaginal cancer

Multidrug-resistant tumours

Phase I

Phase I clinical trial Phase I

Ingenol-3-O-angelate Phenoxodiol

Protopanaxidiol

Skin cancer

Ovarian, prostate, renal, vaginal cancer

Multidrug-resistant tumours

Phase I

Phase I clinical trial Phase I

ment of approx. 12,500 women in the USA alone. Current world demand may touch 250 kg per year. The needles contain equivalent or even higher amounts of 10-deacetyl baccatin III (DAB) in four species of Taxus, T. brevifolia, T. baccata, T. canadensis, T. cuspidata, which is a renewable source. DAB is converted into paclitaxel and into the more potent analogue taxotere [80].

Taxol, which entered the generic drug market in the early 1990s [81], is now largely produced by Taxus cell cultures [82] or by semisynthetic means from advanced precursors (e.g. baccatin III) that are easily available from the needles of Taxus plants as a renewable source [77, 83]. The continuous supply of taxol and its precursors for further synthesis will continue to depend on the plant (needles) or cell-culture system [77, 84] which has become a commercially viable alternative. A paclitaxel production level of 140 to 295 mg/l has been achieved in cell cultures of T baccata, making it a commercially viable production system [82, 85].

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