Topotecan for

As standards digoxin, etoposide, Cyclosporin A, Colchicine (all for MDR 1), Bromosulfophthalein, Furosemide (for MRP2) and Metothrexate, topotecan (for ABCG2) can be used. Efflux ratio of the compound is compared to ratio of standards. 

A 51-year-old woman is being treated with topotecan for refractory ovarian cancer that failed to respond to initial therapy. She wishes to be as aggressive as possible with her therapy and would like you to explain why the recommended dose of topotecan cannot be exceeded. What is the dose-limiting toxicity of topotecan ... 

In 10 women with ovarian cancer amifostine (given daily, before topotecan, for 5 days) did not significantly affect the pharmacokinetics of topotecan. ... 

Forbes, C., Shirran, L., BangnaU, A. M., etal., A rapid and systematic review of the clinical effectiveness and cost effectiveness of topotecan for ovarian cancer. Health Technol. Assess. (2001) 5(28), 1-110. 

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 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... 

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-... 

Topotecan—hold for ANC < 1500 or platelets < 100,000 decrease dose by 0.25 mg/M2/d for prior episode of severe neutropenia or administer G-CSF starting on day 6... 

For other efflux transporters such as BCRP (ABCG2), human pharmacokinetic and pharmacodynamic data are currently rare. However, an investigation of the influence of polymorphisms in ABC-transporter genes on the accumulation of nelfinavir in peripheral blood mononuclear cells (PBMCs) revealed no associations between the polymorphisms in the transporters analyzed and the accumulation of nelfinavir in the PBMCs [151], A second study in patients clearly demonstrated an increase in the AUC of the orally and intravenously administered BCRP substrate topotecan when it is given with GF120918, an inhibitor of P-glycoprotein and BCRP [152],... 

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]. 

Liposomal doxorubicin also received initial approval on the basis of response rafe in patients with refractory cancer followed up with a randomized trial of the agent vs. topotecan. The alkylating agent temozolomide was approved in a Phase 11 trial for treatment of patients with anaplastic astrocytoma. Of note is that, although not yet filed for full approval, temozolomide has been recently added on to radiation therapy (e.g., a major trial of radiation therapy with or without temozolomide) for patients with glioblastoma multiforme. The result of this trial showed a major improvement in survival for patients treated with the radiation plus temozolomide vs. those treated with radiation therapy alone (median survival 15 vs. 12 months, p < 0.0001 and 1 year survival 26 vs. 8%, p < 0.0001).25... 

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. 

Graham MV, Jahanzeb M, Dresler CM, Cooper JD, Emami B, Mortimer JE. Results of a trial with topotecan dose escalation and concurrent thoracic radiation therapy for locally advanced, inoperable nonsmall-cell lung cancer. Int J Radiat Oncol Biol Phys 1996 36(5) 1215-1220. 

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