Phase II Trial of Topotecan in Advanced Breast Cancer

Levine, EG; Cirrincione, C.; Szatrowski, Ted P.; Canellos, George P.; Norton, Larry; Henderson, I. Craig

doi:10.1097/00000421-199906000-00002

Cited by 19 publications

(12 citation statements)

References 13 publications

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“…Levine et al (1999) reported a response rate of 10% in a study of topotecan in relapsed breast cancer conducted by the Cancer and Leukaemia Group B. However, Japanese investigators reported a 23% response rate for the closely related irinotecan in patients with advanced breast cancer (Taguchi et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics

et al. 2003

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Topotecan is currently approved for relapsed small-cell lung cancer and ovarian cancer. Topotecan's efficacy in the second-line setting and novel mechanism of action suggest broad antitumour activity. We utilised a clinically validated, cell-death, ex vivo assay in human tumour explants to examine the activity profile of topotecan alone and in combination with other antitumour agents. Serial dilutions of topotecan alone and in combination with other cytotoxic agents were applied to biopsy specimens of non-small-cell lung cancer (NSCLC) and breast, colon, and prostate cancers. Dose -response curves were interpolated to provide 50% lethal concentrations (LC 50 ). The degree of synergy (by median effect) and normalised Z-scores (raw scores converted to relative activity distributed around the mean) were then computed. Single-agent activity was observed for topotecan in all four tumour types. In 57 chemotherapy-naive specimens, NSCLC revealed the highest activity, demonstrated by the lowest LC 50 value (0.2670.06 mg ml À1 ; P ¼ 0.002). Overall, previously treated and chemotherapy-naive specimens revealed no significant differences in mean LC 50 's. Synergy was observed for several combinations, including topotecan plus cisplatin in prostate and for topotecan plus 5-fluorouracil in breast cancers. The Z-score analyses conducted suggest activity for previously unexplored drug regimens, including topotecan plus 5-fluorouracil, vinorelbine, and mitomycin-C in NSCLC and breast cancer. Phase II studies are underway to determine the degree to which these ex vivo findings will translate into improved clinical results. Topotecan, a semisynthetic, water-soluble derivative of camptothecin, is an inhibitor of topoisomerase I (Kingsbury et al, 1991). This derivative is more stable, has increased solubility, a shorter half-life, and decreased toxicity compared with its parent compound (Verweij et al, 1993;Burke and Mi, 1994;Rothenberg, 1997). Topoisomerase I is a nuclear enzyme that relieves torsional strain on supercoiled DNA and creates single-strand breaks during DNA replication. Topotecan prevents topoisomerase I from repairing the cleaved DNA, which results in double-stranded DNA breaks and eventually apoptosis. The unique mechanism of action of topotecan and lack of clinical crossresistance with other antineoplastic compounds suggest that topotecan has the potential for broad antitumour activity.The activity of topotecan has been demonstrated in several open-label, randomised phase II and III trials. Currently, topotecan is approved for the treatment of relapsed small-cell lung cancer (SCLC) (Eckardt et

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Section: Discussionmentioning

confidence: 99%

Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics

et al. 2003

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“…Significant antitumor activity against metastatic breast cancer was seen only in 2 of several small clinical studies, including one study with brain metastasis patients [30]. The largest study with 53 patients reported objective responses in only 4 patients [31].…”

Section: Chemotherapy For Breast Cancer Brain Metastasesmentioning

confidence: 99%

Chemotherapy for Breast Cancer Brain Metastases

Fenner

Possinger²

2002

Oncol Res Treat

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Breast cancer is the second most common cause of brain metastases, and 10–15% of patients develop clinically overt central nervous system disease. Radiotherapy is the standard treatment for patients with brain metastases. Surgical resection should be considered in patients with isolated brain metastasis and no extracranial disease. The role of chemotherapy in breast cancer brain metastases is not clearly defined; the results of the 8 trials found in the literature are reported. Most experience has been gained with the CMF (cyclophosphamide, methotrexate and fluorouracil) and PE (cisplatin and etoposide) regimens; here the median survival of 6 months is similar to radiotherapy. The blood-brain barrier, maintained by tight endothelial junctions and active transport mechanisms, is a major reason for the lower activity of most chemotherapeutic agents compared to other sites of metastatic disease. Most substances with good penetration of the blood-brain barrier have limited activity against breast cancer and some of the most active substances in breast cancer – including doxorubicine, the taxanes and trastuzumab – appear not to reach the central nervous system in sufficient concentrations. Approaches to overcome the blood-brain barrier are still experimental, and more research is clearly needed to identify chemotherapeutic agents both active in breast cancer and with good penetration of the blood-brain barrier. With the exception of patients with resectable brain metastases, danger of cranial herniation or poor general condition, chemotherapy should be offered to breast cancer patients with brain metastases that have progressive extracranial metastatic disease or relapse after radiotherapy.

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“…TPT has gained approval by Food Drug Administration of the USA for clinical treatment of metastatic ovarian cancer and small cell lung cancer [15][16][17][18][19]. It is also used in the treatment of many other tumors including non-small cell lung cancer [20,21], breast cancer [22], neuroblastoma [23], uterus carcinoma [24], refractory glioblastoma multiforme [25], carcinoma of the uterine cervix [26,27], and chronic myelomonocytic leukemia [28] in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

“…Intravenous TPT treatment can give only 35 −38% response rates in recurrent ovarian carcinoma [40] and ∼10% in breast cancer [22]. Both dose-limiting toxicity (mainly myelosuppression) and tumor resistance are the major reasons for the failure of TPT-based chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Topotecan Is a Substrate for Multidrug Resistance Associated Protein 4

Tian

Zhang²,

Chan³

et al. 2006

CDM

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Topotecan (TPT) is a semisynthetic water-soluble derivative of camptothecin (CPT) used as second-line therapy in patients with metastatic ovarian carcinoma, small cell lung cancer, and other malignancies. However, both dose-limiting toxicity and tumor resistance hinder the clinical use of TPT. The mechanisms for resistance to TPT are not fully defined, but increased efflux of the drug by multiple drug transporters including P-glycoprotein (PgP), multidrug resistance associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) from tumor cells has been highly implicated. This study aimed to investigate whether overexpression of human MRP4 rendered resistance to TPT by examining the cytotoxicity profiles using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide (MTT) assay and cellular accumulation of TPT in HepG2 cells stably overexpressing MRP4. Two kinds of cell lines, HepG2 with insertion of an empty vector plasmid (V/HepG2), HepG2 cells stably expressing MRP4 (MRP4/HepG2), were exposed to TPT for 4 or 48 hr in the absence or presence of various MRP4 inhibitors including DL-buthionine-(S,R)-sulphoximine (BSO), diclofenac, celecoxib, or MK-571. The intracellular accumulation of TPT and paclitaxel (a PgP substrate) by V/HepG2 and MRP4/HepG2 cells was determined by incubation of TPT with the cells and the amounts of the drug in cells were determined by validated HPLC methods. The study demonstrated that MRP4 conferred a 12.03- and 6.86-fold resistance to TPT in the 4- and 48-hr drug-exposure MTT assay, respectively. BSO, MK-571, celecoxib, or diclofenac sensitised MRP4/HepG2 cells to TPT cytotoxicity and partially reversed MRP4-mediated resistance to TPT. In addition, the accumulation of TPT was significantly reduced in MRP4/HepG2 cells compared to V/HepG2 cells, and one-binding site model was found the best fit for the MRP4-mediated efflux of TPT, with an estimated K(m) of 1.66 microM and V(max) of 0.341 ng/min/106 cells. Preincubation of MRP4/HepG2 cells with BSO (200 microM) for 24 hr, celecoxib (50 microM), or MK-571 (100 microM) for 2 hr significantly increased the accumulation of TPT over 10 min in MRP4/HepG2 cells by 28.0%, 37.3% and 32.5% (P < 0.05), respectively. By contrast, there was no significant difference in intracellular accumulation of paclitaxel in V/HepG2 and MRP4/HepG2 cells over 120 min. MRP4 also rendered resistance to adefovir dipivoxil (bis-POM-PMEA) and methotrexate, two reported MRP4 substrates. MRP4 did not exhibit any significant resistance to other model drugs including vinblastine, vincristine, etoposide, carboplatin, cyclosporine and paclitaxel in both long (48 hr) and short (4 hr) drug-exposure MTT assays. These findings indicate that MRP4 confers resistance to TPT and TPT is the substrate for MRP4. Further studies are needed to explore the role of MRP4 in resistance to, toxicity and pharmacokinetics of TPT in cancer patients.

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Phase II Trial of Topotecan in Advanced Breast Cancer

Cited by 19 publications

References 13 publications

Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics

Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics

Chemotherapy for Breast Cancer Brain Metastases

Topotecan Is a Substrate for Multidrug Resistance Associated Protein 4

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