Topotecan

Sample preparation Vortex 200 lL plasma with 800 aL cold (dry ice) MeOH for 10 s, centrifiige at 7000 g for 2 min. Dilute 2 vol of supernatant with 1 vol of water (to measure lactone form) or 1.5% phosphoric acid (to measure total amount), inject a 20 p,L aliquot. 

Mobile phase MeOHibuffer 27 73 (The buffer was 75 mM potassium dihydrogen phosphate containing 0.2% triethylamine, adjusted to pH 6.5 with KOH.) 

Kirstein, M.N. Hanna, S.K. lacono, L.C. Johnston, B. Stewart, C.F. Determination of plasma topotecan and its metabolite Al-desmethyl topotecan as both lactone and total form by reversed-phase liquid chromatography with fluorescence detection, J.Chromatogr.B, 2003, 784, 225-232. 

Sample preparation Vortex 900 itL plasma with 100 LL buffer for 20 s. Add a 200 [xL aliquot to 800 LL cold (-40°) MeOH, vortex for 20 s, centrifuge for 2 min. Mix a 500 [xL aliquot of the supernatant with 500 ixL buffer, inject a 200 xL aliquot. (The buffer was 8 mM disodium hydrogen phosphate containing 1 mM potassium dihydrogen phosphate, 137 mM NaCl, and 3 mM KCl and was adjusted to pH 2.0 for lactone or pH 11.0 for carboxylate forms.) 

Guard column Guard-Pak C18 NovaPak Column 150 x 3.9 4 xm NovaPak C18 

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BCRP (ABCG2) Cisplatin, folate, methotrexate, mitoxantrone, topotecan, irinotecan, steroids (cholesterol, testosterone, progesterone), certain chlorophyll metabolites, and others... 

Camptothecins (irinotecan, topotecan) are derived from the bark of the Chinese tree Xi Shu (Camptotheca accuminata). They inhibit topoisomerase I thus effecting double strand breaks. Unwanted effects include diarrhea and reversible bone marrow depression. 

The first clinical trials were performed in the 1970 s using a sodium salt derivative with an open E-ting (Fig. 1). However, the clinical efficacy was limited and severe bladder toxicity led to the termination of the clinical trials. The poor efficacy of the camptothecin sodium salt in those clinical trials was probably due to the fact that the open E-ring form of camptothecin (carboxylate derivative) is inactive as a Topi inhibitor. Following the identification of Topi as a target of camptothecin, water-soluble derivatives were produced by the pharmaceutical industry. Two of these water-soluble derivatives have been approved by the FDA for cancer treatment in the early 2000s topotecan and irinotecan. 

Irinotecan (CPT-11) is approved for colorectal tumors. It is given by intravenous infusion. The most severe side effect is diarrhea, which can be severe and needs to be treated by a physician. Temporary liver dysfunction is generally asymptomatic. The other side effects are the same as those produced by topotecan. 

This is an inverted parabolic relation in terms of ttx (calculated hydrophobic parameter of the substituents), which suggests that activity of these compounds first decreases as the hydrophobicity of substituents increases and after a certain point (inversion point ttx = 0.67), activity begins to increase. This may correspond to an allosteric reaction [54]. The indicator variable I is assigned the value of 1 and 0 for the presence and absence of N(CH3)2 substituent at the X position. Its positive coefficient suggests that the presence of a N(CH3)2 substituent at X position, increases the activity. REC is the relative effective concentration i.e., concentration relative to topotecan, whose value is arbitrarily assumed as 1, that is able to produce the same cleavage on the plasmid DNA in the presence of human topo I. 

Topotecan inhibits topoisomerase I to cause single-strand breaks in DNA. The pharmacokinetics of topotecan can be described by a two-compartment model, with a terminal half-life of 80 to 180 minutes, with renal clearance accounting for approximately 70% of the clearance.19 Topotecan has shown clinical activity in the treatment of ovarian and lung cancer, myelodysplastic syndromes, and acute myelogenous leukemia. The intravenous infusion may be daily for 5 days or once weekly. Side effects include myelosuppression, mucositis, and diarrhea. 

Topotecan Topotecan 1.5 mg/m2 IV over 30 minutes (days 1-5) 21 days 18% 70%... 

Topotecan Neutropenic fever, neutropenic sepsis, anemia, thrombocytopenia, nausea, fatigue, vomiting, stomatitis, anorexia, diarrhea, fever Mild (days 1-5)... 

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. 

Topotecan 1.5 mg/m2 IV infused over 30 minutes on days 1,2,3, 4, 5 repeat every 21 days or 4 mg/m2 IV infused over 30 minutes once a week for 3 consecutive weeks, followed by 1 week rest 6.5%—1 7% 31% Myelosuppression (DLT), nausea/vomiting, diarrhea, Stomatitis, abdominal pain, alopecia, SGOT/SGPT elevation 1. Give proper dosing for renal dysfunction... 

In a similar way (and as described for the aromatic isocyanides), aliphatic a, 3-un-saturated isocyanides can also be used, leading to similar structures with a cyclo-hexano instead of a benzo moiety [84]. Based on the approach using aromatic isocyanides, a small library of about 20 camptothecin derivatives has been prepared, of which irinotecan and topotecan have entered the clinical treatment of cancer [85]. For the synthesis of the camptothecin derivatives, 3-206 was alkylated with the appropriate propargylic bromides 3-207 to give 3-208, which were irradiated in benzene at 70 °C, together with the respective isocyanide 3-209 and hexamethylditin... 

Brinkhuis, R. F., Maliepaard, M., Beijnen, J. H. et al., Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan, J. Natl. Cancer Inst. 2000, 92, 1651-1656. 

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-... 

Maliepaard M, van Gastelen MA, de Jong LA, Pluim D, van Waardenburg RC, Ruevekamp-Helmers MC et al. Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res 1999 ... 

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