Topotecan drug

Breast Cancer Resistance Protein (BCRP, also known as MXR or ABCP), first cloned from mitoxantrone and anthracycline-resistant breast and colon cancer cells [188, 189] is a half-transporter efflux pump believed to function as a homo-or hetero-dimer. Following its identification, BCRP-mediated drug resistance was observed for topoisomerase inhibitors including camptothecins [190, 191] and in-dolocarbazoles [192]. In normal tissues, BCRP was detected in placental syncytio-trophoblasts, hepatocyte canalicular membrane, apical intestinal epithelia and vascular endothelial cells [193]. These findings support the important role BCRP plays in modulating topotecan bioavailability, fetal exposure and hepatic elimination [194]. Considering that the substrates and tissue distributions for BCRP overlap somewhat with MDR1 and MRPs [195], additional studies will be required to define the relative contribution of each of these transporters in the overall and tis-... 

First generation of topi inhibitors were developed as drugs from camptothecins, a family of compounds derived from wood and bark of the Chinese tree Camptotheca acuminata) [9, 10], Many of these are already in clinical use or clinical trials, including irinotecan, topotecan, exatecan, rubitecan, and lurtotecan. Irinotecan (CPT-11) is bioactivated in liver by carboxylesterase to the active metabolite SN-38, 1000-fold more active [11]. Irinotecan received in 1998 FDA approval for treatment of metastatic colorectal cancer after failure of treatment with 5FU [12],... 

Topotecan is the second camptothecin derivative it is itself an active drug, and received FDA approval as second line therapy in metastatic ovarian cancer (1996) and in SCLC (1998) [13], In addition, representatives of a second generation of topi inhibitors, the homocamptothecins, are now being developed for chemotherapy, e.g., BN-80915 and BN-809271 [14]. 

Liu JJ, Hong RL, Cheng WF, et al. Simple and efficient liposomal encapsulation of topotecan by ammonium sulfate gradient stability, pharmacokinetic and therapeutic evaluation. Anti-Cancer Drugs 2002 13(7) 709. 

Anticancer drugs Daunorubicin Topotecan 9-Aminocamptothecin SN-38 (iiinotecan metabolite) Epirubicin Mitoxantrone Methotrexate Imatinib Gefitinib (i)... 

ABCG2 Topotecan Increased accumulation of drug in cells (94) Increased bioavailability in (94)... 

In recent years, however, some of the greatest emphasis has been placed on the search for anticancer and antiviral agents derived from natural products. Success in that area has not heen as great as that achieved in other helds. Since 1960, only seven plant-derived drugs have heen approved by the FDA for use as anticancer agents. Four of those drugs, vinblastine, vincristine, etoposide, and teniposide, were discovered in the 1950s. The last three—Taxol , topotecan, and irinotecan—were discovered and approved much more recently. 

UCN-01 is currently being explored in cancer patients in Phase I/II clinical trials, both as a single agent and in combination with conventional chemotherapeutic drugs (e.g., cytarabine, topotecan). In this last scenario, results from a Phase I clinical trial in combination with topotecan showed antitumor activity in 12 patients with advanced solid tumor with one partial response and three cases of stable disease. However, and due to the low selectivity of UCN-01, it is unclear which inhibited kinase(s) are suppressing growth and survival of cancer cells in these clinical studies. 

Reconstitution of full-length BRCAl into mouse embryonic fibroblast cells with a disrupted BRCAl led to an increase in resistance to several DNA damaging agents, including the platinum compounds carboplatin and oxaliplatin, the topoisomerase 1 drugs irinotecan and topotecan, and the topoisomerase 11 drugs doxorubicin and etoposide (61). 

VM-26, 2), Taxol (paclitaxel), navelbine (Vinorelbine), taxotere (Docetaxel), topotecan (Hycamtin), and irinotecan (Camptosar). The last three drugs were approved by the Food and Drug Administration in 1996. 

Other drugs classified as plant alkaloids include etoposide, irinotecan, teniposide, and topotecan (see Table 36 1). These drugs inhibit specific enzymes known as topoisomerase enzymes, which are necessary for DNA replication.11 Inhibition of these enzymes causes a break in both strands of the DNA double helix, which leads to DNA destruction and cell death. Etoposide and teniposide inhibit the topoisomerase I form of this enzyme, and irinotecan and topotecan inhibit the topoisomerase II form of this enzyme. These drugs are therefore used to limit cell division and cancer growth in various types of neoplastic disease (see Table 36-4). 

It has been used to treat leukemia. Other anticancer drugs have been modified from Camptotheca acuminata. Topotecan is used to treat ovarian and small-lung cancers. Irinotecan is used to treat metastatic colorectal cancer. 

Fleck C, Hilger R, Jurkutat S, et al. Ex vivo stimulation of renal transport of the cytostatic drugs methotrexate, cisplatin, topotecan (Hycamtin) and raltitrexed (Tomudex) by dexamethasone, T3 and EGF in intact human and rat kidney tissue and in human renal cell carcinoma. Urol Res 2002 30 256-262. 

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