Vincristine Etoposide

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. 

Five of thirty-two patients treated with the alternating drug regimen CAMBO-VIP (cyclophosphamide, doxorubicin, methotrexate, bleomycin, vincristine, etoposide, ifosfamide, and prednisolone) for non-Hodgkin s lymphoma developed blisters under the thickened skin of the palms and/or soles, followed by desquamation (28). 

MRP3 GSH conjugates, glucuronides, sulfate conjugates, methotrexate, monoanionic bile acids (taurocholate, glycocholate), vincristine, etoposide MK571 ( )... 

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. 

In addition to the drugs mentioned above (doxorubicin, 5-fluoruracil, methotrexate, and cyclophosphamide), researchers have found other chemotherapy compounds to be common in studies that looked at problems with language, memory, and other cognitive abilities. These drugs include cisplatin, vincristine, etoposide, vinblastine, and steroids such as dexamethasone and prednisone. Their relative risks associated with later cognitive impairment, however, have not been well established. 

The efficacy of doxorubicin can be increased by verapamil and nicardipine in doxorubicin-resistant tissue culture systems, while nifedipine has only minimal activity. A study in five patients with small cell lung cancer given doxorubicin, vincristine, etoposide and cyclophosphamide showed that when they were given verapamil 240 to 480 mg daily the AUC of doxorubicin was doubled, its peak serum levels were raised and its clearance was reduced. No increased toxicity was seen in this study. However, although another study found no increase in non-cardiac toxic-ities, verapamil caused an unacceptable degree of cardiac toxicity. Be alert for this possibility if both drugs are used. 

MANAGING ALOPECIA. Alopecia (loss of hair) is a common adverse reaction associated with some of the antineoplastic drugs. Some drugs cause severe hair loss, whereas others cause gradual thinning. Examples of drug commonly associated with severe hair loss are doxorubicin and vinblastine Methotrexate, bleomycin, vincristine, and etoposide are associated with gradual hair loss. 

CAV, cyclophosphamide, doxorubicin, vincristine EC, etoposide carboplatin EP, etoposide cisplatin IC, irinotecan, cisplatin. See Table 87M for doses and schedules. 

More recently, a German study compared a dose-escalated regimen of BEACOPP (with filgrastim support) with standard-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, gemcitabine (BEACOPP) and COPP alternating with ABVD (C—cyclophosphamide instead of mechlorethamine for MOPP).18 The escalated BEACOPP was... 

LL, a 47-year-old man, was diagnosed with high-risk diffuse large cell B-cell non-Hodgkin s lymphoma (NHL) 12 months ago. LL had a complete response to his initial treatment of six cycles of RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). LL is participating in a clinical trial and is randomized to receive a myeloablative autologous HCT TBI days 8 to 5, etoposide day 4, rest day 3, cyclophosphamide day 2, rest day 1, with infusion of autologous PBPC on day 0. 

Standard combination regimens (e.g., CHOP) yield disappointing results. Newer approaches including dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), and rituximab-containing combination chemotherapy are promising. 

Anticancer drugs Paclitaxel Docetaxel Vinblastine Vincristine Tipifarnib Diflomotecan Iiinotecan Doxorubicin Daunorubicin Etoposide Tenoposide Tamoxifen (i)... 

Anticancer drugs Methotrexate Doxorubicin Daunorubicin Epirubicin Etoposide Vincristine Vinblastine Paclitaxel Iiinotecan... 

Doxorubin Etoposide Methotrexate Mitoxantrone Cisplatin Vincristine Vinblastine Iiinotecan ... 

The vinca alkaloids vinblastine and vincristine are capable of producing the MDR phenotype in a wide variety of cell types. Furthermore, cells that are made resistant to antitumor drugs such as doxorubicin, actinomy-cin D, or the epipodophyllotoxins etoposide (VP-16) and teniposide (VM-26) are often resistant to the effects of the bisindole alkaloids. The structural and mechanistic diversity of these compounds is even more striking against the backdrop of collateral resistance. 

Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Use aprepitant with caution in patients receiving concomitant medicinal products, including chemotherapy agents that are primarily metabolized through CYP3A4 (docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine). 

Aprepitant may be affected by paroxetine, CYP2C9 substrates (eg, phenytoin, tolbutamide, warfarin), CYP3A4 substrates (eg, alprazolam, cisapride, dexamethasone, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, methylprednisolone, midazolam, paclitaxel, pimozide, triazolam, vinblastine, vincristine, vinorelbine), and oral contraceptives. 

Short term treatment with TPA sensitized human 2008 ovarian carcinoma cells to cis-platin. This sensitization disappeared completely by seven hours after treatment, indicating that not inhibition, but activation of PKC sensitizes 2008 cells to the antiproliferative activity of cis-platin (Isonishi et al., 1990). Pretreatment of HeLa cells with TPA or PdBu caused a 9-fold increase in cellular sensitivity to cis-platin and 2.5-fold to melphalan, but had now effect on the antiproliferative activity of bleomycin, adriamycin, vincristine, or mitomycin C. The sensitization of HeLa cells by TPA was associated with a 6-fold stimulation of PKC activation and a concentration- and time-dependent increase in cellular platinum content. (Basu et al. 1990). PKC activity was found to be decreased significantly in cis-platin-resistant human small cell lung H69/CP cancer cells compared to the drug-sensitive variant. A similar reduction in PKC activity was noted in ovarian carcinoma 2008 cells that were resistant to cis-platin. A modest decrease in PKC activity was also observed in etoposide-resistant H69 cells but not in taxol-resistant H69 cells or bleomycin-resistant human head and neck carcinoma A-253 cells (Basu et al., 1996), indicating that reduced PKC activity leads to decreased sensitivity in this system. 

CAV = cyclophosphamide/doxorubicin/vincristine CEV = cyclophosphamide/epirubicin/vincristine CCM = cyclophosphamide/lomustine/methotrexate EA = etoposide/doxorubicin VMV/VAC = vincristine, methotrexate, VP-16/vincristine, doxorubicin, cyclophosphamide VAP = vincristine/doxorubicin/ procarbazine PE = cisplatin/etoposide. 

Other studies evaluated the question of whether early delivery of radiation concurrently with chemotherapy was better than late delivery. A study performed by the C ALGB randomized patients to early (d 1, cycle 1), late (d 64, cycle 4), or no radiation therapy. The radiation therapy dose was 50 Gy over 6 wk. Chemotherapy used in this trial was cyclophosphamide, etoposide, and vincristine. The local recurrence rate for the early, late, and no radiation therapy arms was 49%, 68%, and 82%, respectively. The 2-yr progression-free survival rate was 15% for the early schedule arm vs 25% for the late schedule (p = 0.078). The 5-yr survival rate for the early, late, and no radiation therapy arms was 6.6%, 12%, and 3%, respectively (p = 0.007). The poor 5-yr survival rate for the early schedule was felt to be due to the significant decrease in chemotherapy dose needed for the early schedule group (4,49). 

The NCIC randomized patients to radiation therapy started either early or late with concurrent chemotherapy (cyclophosphamide, doxorubicin, and vincristine alternating with cisplatin and etoposide) (6). The radiation therapy dose was 40 Gy given in 15 fractions over three weeks with the cisplatin and etoposide portion of the chemotherapy. In the early arm the radiation was started on d 21 of cycle 2 (after the first cycle... 

Aprepitant (Emend) [Centrally Acting Antiemetic] Uses Pre-vents N/V assoc w/ emetogenic CA chemo (eg, cisplatin) (use in combo w/ other antiemetics) Action Substance P/neurokinin l(NKi) receptor antagonist Dose 125 mg PO day 1, 1 h before chemo, then 80 mg PO qAM days 2 3 Caution [B, /-] Contra Use w/ pimozide, Disp Caps SE Fatigue, asthenia, hiccups Interactions T Effects W/ clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin T effects OF alprazolam, astem-izole, cisapride, dexamethasone, methylprednisolone, midazolam, pimozide, terfe-nadine, triazolam, chemo agents, eg, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, vinblastine, vincristine, vinorelbine i effects W/ paroxetine,... 

Three classes of plant-derived drugs, the vinca alkaloids (vincristine, vinblastine, and vinorelbine), the epipodo-phyllotoxins (etoposide and teniposide and the tax-anes (paclitaxel and taxotere), are used in cancer chemotherapy. These classes differ in their structures and mechanisms of action but share the multidrug resistance mechanism, since they are all substrates for the multidrug transporter P-glycoprotein. 

PCV Procarbazine, lomustine, vincristine PEB Cisplatin (platinum), etoposide, bleomycin... 

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). 

Since 1961, nine plant-derived compounds have been approved for use as anticancer drugs in the U.S. vinblastine (Velban), vincristine (Oncovin), etoposide (VP-16,1), teniposide... 

Another area in which natural products have had a major impact on longevity and quality of life is in the chemotherapy of cancer. In fact, most major anticancer drugs are derived from plants or microorganisms (see Chapter 62). Examples include bleomycin, doxorubicin, daunorubicin, vincristine, vinblastine, mitomycin, streptozocin, and most recently, additions of paclitaxel (Taxol ), ironotecan (a camptothecin derivative), and etoposide and tenoposide (podophyllo-toxin derivatives). 

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