3] Plant-derived compounds have also been an important source of several clinically useful anticancer agents, which include vinblastine, vincristine, the camptothecin derivatives, topotecan and irinotecan, etoposide derived from epipodophyllotoxin
, and paclitaxel (taxol).
For example, piperonyl butoxide, isosafrole, kavalactones, podophyllotoxin, and epipodophyllotoxin
are involved in the inhibition of CYP activity (Mathews et al.
Several anticancer agents including Taxol, vinblastine, vincristine, the camptothecin derivatives, topotecan and irinotecan, and etoposide derived from epipodophyllotoxin
are in clinical use all over the world.
4,16,17) The risk depends on the type of epipodophyllotoxin
infusion, combination of several alkylating agents or presence of polymorphism in the thiopurine methyltransferase (TPMT) gene for 6-mercaptopurine.
Patients treated with high-dose radiotherapy to extended treatment volumes have the highest risk of this complication; alkylating-agent and epipodophyllotoxin
chemotherapy may enhance radiotherapy-induced carcinogenesis in the lungs and gastrointestinal tract.
On the other hand, the variant allele was observed to be a protective factor for treatment-related leukemia, whereas the wild-type allele for this polymorphism of CYP3A4 was associated with increased metabolism of epipodophyllotoxin
, a chemotherapy agent, leading to leukemas with MLL gene translocations (6).
The best known are the Vinca alkaloids, vinblastine and vincristine, isolated from Catharanthus roseus, etoposide and teniposide, which are semi-synthetic derivatives of the natural product epipodophyllotoxin
, Paclitaxel isolated from the bark of Taxus brevifolia, the semi-synthetic derivatives of camptothecin, irinotecan and topotecan, isolated from Cam ptotheca acuminata, among several others (Cragg et al.
Multidrug resistance protein 1 (MRP1), which is structurally similar to P-gp, is the product of the ABCC1 gene and can export anthracenedione, anthracycline, epipodophyllotoxin
, vinca alkaloids, etc.
O- demethylation of epipodophyllotoxins
is catalyzed by human cytochrome P450 3A4.
Chemo-immunotherapy based on the HLH-2004 protocol includes corticosteroids, epipodophyllotoxins
, and cyclosporine, and succeeds in controlling the disease in the majority of patients; however, cure is rarely achieved.
Defects in the normal DNA repair process further contributes to the development microsatellite instability, together known as a possible factors associate with development of epipodophyllotoxins
resistance in breast cancer cells [12, 13].
Acute myeloid leukemia in children treated with epipodophyllotoxins
for acute lymphoblastic leukemia.