Topotecan + vincristine

The treatment of recurrent disease depends on the time to recurrence. If the time to recurrence is less than 6 months, second-line therapy should be considered if the patient has an acceptable performance status (see Patient Care and Monitoring ). The most widely accepted second-line therapies in SCLC are topotecan alone or CAV [cyclophosphamide, doxorubicin (Adriamycin), vincristine]. Relapses occurring more than 6 months after treatment warrant a repeat of the initial regimen. Poor performance status patients (3—4) typically are treated with palliative care therapies. 

Recurrent SCLC is usually less sensitive to chemotherapy. If recurrence is more than 6 months after induction chemotherapy, the original regimen can be repeated. If recurrence occurs in less than 6 months but >3 months, treatment options include a taxane, gemcitabine, topotecan, irinotecan, CAV (cyclophosphamide, doxorubicin, and vincristine), and vinorelbine. 

Figure 1 Chemical structures of some amphipathic weak bases that have been loaded and stabilized in liposomes using trialkylammonium salts of polyanionic trapping agents in our lab. (A) Doxorubicin, (B) epirubicin, (C) vinorelbine, (D) vincristine, (E) vinblastine, (E) topotecan, (G) irinotecan, (H) swainsonine, (I) 2-diethylami-noethyl-ellipticinium, (J) 6-(3-aminopropyl)ellipticine, and (K) LAQ824.

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. 

In the anticancer area, the use of natural products as direct agents or as novel lead compounds for the generation of synthetic or semisynthetic analogs has proved remarkably productive, and a recent survey showed that 62% of new anticancer agents over the last 10 years have been natural products or agents based on natural product models.7 Examples of clinically important plant-derived natural products are the vinca alkaloids vinblastine (4) and vincristine (5), the podophyllotoxin analogs etoposide (6) and teniposide (7), the diterpenoid paclitaxel (Taxol ) (8), and the camptothedn-derivative topotecan (9). 

Fig. 3 Venn-diagram for selected compounds interacting with the key MDR-related ABC transporters. MDR-substrate anticancer agents. Abbreviations VCR vincristine, VP-16 etoposide, STER steroids, TAM tamoxiphen, TKI-INHIB tyrosin kinase inhibitors e.g. STI-571, DOX doxorubicine or adriamycin, DNR daunorubicin, EPIR epirubicin, MX mitoxantrone, TOPOT topotecan, iridotecan, BISANT bisanthrone, COLCH colchicin, ACT-D actinomycin D, MYTOM mytomycin, TX methotrexate, CPHAM cyclophosphamide, CHLB chlorambucil, CARM carmustine, LCV leucovorin, HUR hydroxy urea, CISPL cisplatin, TAXOL paclitaxel. (Reproduced from [4])...

Cell Line Melphalan P2 Sarcolysine Doxorubicin Vincristine Topotecan... 

Actinomycin D, bisantrene, chlorambncil, cisplatin, cytarabine, dannornbicin, docetaxel, doxorubicin, epirn-bicin, etoposide, flnoro uracil, hydroxyurea, mitomycin C, mitoxantrone, paclitaxel, tamoxifen, topotecan, taxol, vinblastine, vincristine. 

Camptothecin analogs Irinotecan Topotecan Epipodophyllotoxins Etoposide Teniposide Antitumor antibiotics Bleomycin Dactinomycin Daunorubicin Doxorubicin Epirubicin Idarubicin Mitomycin Mitoxantrone Valrubicin Microtubule agents Docetaxel Paclitaxel Vinblastine Vincristine Vinorelbine Enzymes Asparaginase Pegasparaginase Metals... 

Fluorouracil Glucocorticoids Indinavir Loperamide Losartan Methotrexate Mitoxantrone Nelfinavir Paclitaxel Ritonavir Saquinavir Sirolimus Tacrolimus Topotecan Vinblastine Vincristine Vindesine Vinorelbine Verapamil ... 

The study of natural products, or Nature s Combinatorial Library , has had a long history as a source of drugs, and plants have historically been at the forefront of natural product drug discovery. In the anticancer area, for example, vinblastine and vincristine, etoposide, paclitaxel (Taxol), docetaxel, topotecan, and irinotecan, among others, are all plant-derived natural products or modified versions of plant compounds, while antimalarial therapy would be much poorer without quinine and artemisinin and the drugs derived from these plant products. This chapter provides an overview of the major medicinal agents that are themselves natural products isolated from plants or are chemical modifications of such lead compounds. It covers the therapeutic areas of cancer, HIV, malaria, cardiovascular, and central nervous system (CNS) diseases. Natural plant products have also made contributions in areas such as immunomodulatory and antibiotic activities," and the reader is referred to the cited reviews for information on these areas. 

Although not listed in the tables, at least four other natural product drugs have given yeoman service in the antitumor area. The first of these is paclitaxel (Taxol ) which sold US 1.6 billion in 2000 this is followed by the vinca alkaloids vinblastine and vincristine. Completing the quartet are the natural product-derived epi-podophyllotoxin derivatives teniposide and etoposide and the materials derived from camptothecin, topotecan and CPT-11. These will probably not be the only natural product drugs in the antitumor field, as can be seen by inspection of Table 6.3, where Cragg and Newman recently reported on the source... 

Among all ABC transporters, P-gp, also known as MDRl protein, ABCBl or CD243, is probably the most studied and characterized member. It was first found as a 170-kDa ATP-dependent membrane glycoprotein that acts as a drug efflux pump [15], P-gp is a broad-spectrum transporter, capable of transporting several structurally and functionally unrelated substrate molecules. Its substrates are typically hydrophobic, amphipathic products, including many chemotherapeutic compounds used for cancer treatment, e.g., vinca alkaloids (vincristine, vinblastine), taxanes (paclitaxel, docetaxel), epipodophyllotoxins (etoposide, teniposide), anthracyclines (doxorubicin, daunorubicin, epirubicin), topotecan, dactinomycin, and mitomycin-C [37]. 

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