Showing papers on "Topotecan published in 2000"

Antitumor Effect and Potentiation of Cytotoxic Drugs Activity in Human Cancer Cells by ZD-1839 (Iressa), an Epidermal Growth Factor Receptor-selective Tyrosine Kinase Inhibitor

Abstract: Transforming growth factor alpha (TGF-alpha) is an autocrine growth factor for human cancer. Overexpression of TGF-alpha and its specific receptor, the epidermal growth factor receptor (EGFR), is associated with aggressive disease and poor prognosis. The EGFR has been proposed as a target for anticancer therapy. Compounds that block ligand-induced EGFR activation have been developed. ZD-1839 (Iressa) is a p.o.-active, quinazoline derivative that selectively inhibits the EGFR tyrosine kinase and is under clinical development in cancer patients. The antiproliferative activity of ZD-1839 alone or in combination with cytotoxic drugs differing in mechanism(s) of action, such as cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, doxorubicin, etoposide, topotecan, and raltitrexed, was evaluated in human ovarian (OVCAR-3), breast (ZR-75-1, MCF-10A ras), and colon cancer (GEO) cells that coexpress EGFR and TGF-alpha. ZD-1839 inhibited colony formation in soft agar in a dose-dependent manner in all cancer cell lines. The antiproliferative effect was mainly cytostatic. However, treatment with higher doses resulted in a 2-4-fold increase in apoptosis. A dose-dependent supra-additive increase in growth inhibition was observed when cancer cells were treated with each cytotoxic drug and ZD-1839. The combined treatment markedly enhanced apoptotic cell death induced by single-agent treatment. ZD-1839 treatment of nude mice bearing established human GEO colon cancer xenografts revealed a reversible dose-dependent inhibition of tumor growth because GEO tumors resumed the growth rate of controls at the end of the treatment. In contrast, the combined treatment with a cytotoxic agent, such as topotecan, raltitrexed, or paclitaxel, and ZD-1839 produced tumor growth arrest in all mice. Tumors grew slowly for approximately 4-8 weeks after the end of treatment, when they finally resumed a growth rate similar to controls. GEO tumors reached a size not compatible with normal life in all control mice within 4-6 weeks and in all single agent-treated mice within 6-8 weeks after GEO cell injection. In contrast, 50% of mice treated with ZD-1839 plus topotecan, raltitrexed, or paclitaxel were still alive 10, 12, and 15 weeks after cancer cell injection, respectively. These results demonstrate the antitumor effect of this EGFR-selective tyrosine kinase inhibitor and provide a rationale for its clinical evaluation in combination with cytotoxic drugs.

Role of Breast Cancer Resistance Protein in the Bioavailability and Fetal Penetration of Topotecan

Abstract: Background and Methods: Breast cancer resistance protein (BCRP/MXR/ABCP) is a multidrug-resistance protein that is a member of the adenosine triphosphate-binding cassette family of drug transporters. BCRP can render tumor cells resistant to the anticancer drugs topotecan, mitoxantrone, doxorubicin, and daunorubicin, To investigate the physiologic role of BCRP, we used polarized mammalian cell lines to determine the direction of BCRP drug transport. We also used the BCRP inhibitor GF120918 to assess the role of BCRP in protecting mice against xenobiotic drugs. Bcrp1, the murine homologue of BCRP, was expressed in the polarized mammalian cell lines LLC-PK1 and MDCK-II, and the direction of Bcrp1-mediated transport of topotecan and mitoxantrone was determined. To avoid the confounding drug transport provided by P-glycoprotein (P-gp), the roles of Bcrp1 in the bioavailability of topotecan and the effect of GF120918 were studied in both wild-type and P-gp-deficient mice and their fetuses. Results: Bcrp1 mediated apically directed transport of drugs in polarized cell lines, When both topotecan and GF120918 were administered orally, the bioavailability (i,e,, the extent to which a drug becomes available to a target tissue after administration) of topotecan in plasma was dramatically increased in P-gp-deficient mice (greater than sixfold) and wild-type mice (greater than ninefold), compared with the control (i,e., vehicle-treated) mice. Furthermore, treatment with GF120918 decreased plasma clearance and hepatobiliary excretion of topotecan and increased (re-)uptake by the small intestine. In pregnant GF120918-treated, P-gp-deficient mice, relative fetal penetration of topotecan was twofold higher than that in pregnant vehicle-treated mice, suggesting a function for BCRP in the maternal-fetal barrier of the placenta. Conclusions: Bcrp1 mediates apically directed drug transport, appears to reduce drug bioavailability, and protects fetuses against drugs. We propose that strategic application of BCRP inhibitors may thus lead to more effective oral chemotherapy with topotecan or other BCRP substrate drugs.

ZD1839 (‘Iressa’)1,2 as an Anticancer Agent

Abstract: ZD1839 (‘lressa’)1,2 is an orally active, selective epidermal growth factor receptor-tyrosine kinase inhibitor which blocks signal transduction pathways implicated in the proliferation and survival of cancer cells and other host-dependent processes promoting cancer growth. In preclinical studies, ZD1839 produced reversible growth inhibition and growth delay in a wide range of tumour cell lines and human tumour xenografts. Moreover, this activity was enhanced when ZD1839 was coadministered with cytotoxic agents. Preliminary results from phase I trials in patients with advanced disease and a wide variety of tumour types suggest that ZD1839 has an acceptable tolerability profile and promising clinical efficacy, particularly in non-small cell lung cancer (NSCLC). ZD1839 is currently in phase III clinical development for the treatment of advanced NSCLC. In addition, further trials are ongoing or planned in a number of other tumour types.

Topotecan Has Substantial Antitumor Activity as First-Line Salvage Therapy in Platinum-Sensitive Epithelial Ovarian Carcinoma: A Gynecologic Oncology Group Study

Abstract: PURPOSE: Topotecan is known to be active in recurrent ovarian cancer, but most prior studies have focused on platinum-resistant or refractory populations. This study was undertaken to define the response rate and progression-free interval in platinum-sensitive patients. PATIENTS AND METHODS: Patients with recurrent ovarian cancer after one or two prior chemotherapy regimens and in whom the interval between prior platinum therapy and the initiation of protocol therapy was greater than 6 months were treated with topotecan 1.5 mg/m2 intravenously over 30 minutes daily for 5 days, with this cycle repeated every 21 days. RESULTS: Forty-eight patients were entered onto the study; 47 were assessable for toxicity and 46 for response. The response rate was 33% (two complete responses and 13 partial responses), with a median response duration of 11.2 months. Hematologic toxicity predominated but was manageable in most patients with frequent incorporation of cytokines and RBC and platelet transfusions. Fatigue was r...

Liposomal encapsulation of topotecan enhances anticancer efficacy in murine and human xenograft models.

Abstract: Topotecan was encapsulated in sphingomyelin/cholesterol liposomes using an ionophore-generated proton gradient. After i.v. injection, liposomal topotecan was eliminated from the plasma much more slowly than free drug, resulting in a 400-fold increase in plasma area under the curve. Further, high-performance liquid chromatography analysis of plasma samples demonstrated that topotecan was protected from hydrolysis within the liposomal carrier with >80% of the drug remaining as the active, lactone species up to 24 h. The improved pharmacokinetics observed with liposomal topotecan correlated with increased efficacy in both murine and human tumor models. In the L1210 ascitic tumor model, optimal doses of liposomal topotecan resulted in a 60-day survival rate of 60-80%, whereas in a L1210 liver metastasis model, 100% long-term survival (>60 days) was achieved. In contrast, long-term survivors were rarely seen after treatment with free topotecan. Further, in a human breast carcinoma model (MDA 435/LCC6), liposomal topotecan provided greatly improved increase in life span relative to the free drug. These results suggest that liposomal encapsulation can significantly enhance the therapeutic activity of topotecan.

The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity.

Abstract: We describe the rational design and synthesis of B- and A, B-ring-modified camptothecins. The key alpha-hydroxy-delta-lactone pharmacophore in 7-tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67, 14) displays superior stability in human blood when compared with clinically relevant camptothecin analogues. In human blood 14 displayed a t(1/2) of 130 min and a percent lactone at equilibrium value of 30%. The tert-butyldimethylsilyl group renders the new agent 25-times more lipophilic than camptothecin, and 14 is readily incorporated, as its active lactone form, into cellular and liposomal bilayers. In addition, the dual 7-alkylsilyl and 10-hydroxy substitution in 14 enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions together function to promote the enhanced blood stability. In vitro cytotoxicity assays using multiple different cell lines derived from eight distinct tumor types indicate that 14 is of comparable potency to camptothecin and 10-hydroxycamptothecin, as well as the FDA-approved camptothecin analogues topotecan and CPT-11. In addition, cell-free cleavage assays reveal that 14 is highly active and forms more stable top1 cleavage complexes than camptothecin or SN-38. The impressive blood stability and cytotoxicity profiles for 14 strongly suggest that it is an excellent candidate for additional in vivo pharmacological and efficacy studies.

Prevention of phosphatidylinositol 3'-kinase-Akt survival signaling pathway during topotecan-induced apoptosis.

Abstract: The serine/threonine kinase Akt (also known as protein kinase B) is a downstream effector of phosphatidylinositol-3'-kinase [PI(3)K] that is recognized as the major mediator of survival signals that protect cells from undergoing apoptosis. In the course of examining the target molecules of the topoisomerase I inhibitor topotecan, we found that topotecan treatment promoted Akt dephosphorylation that led to the inactivation of Akt in human lung cancer A549 cells. Transfection of the constitutively active akt cDNA into A549 cells resulted in the reduction of the cytotoxic effect of topotecan, indicating that inhibition of the Akt pathway played an important role in exhibition of topotecan-mediated cytotoxic effects. Further analysis of Akt dephosphorylation revealed that topotecan treatment suppressed upstream kinases of Akt, 3-phosphoinositide-dependent protein kinase 1, and PI(3)K. Overall, the results demonstrate that topotecan exhibited its cytotoxic effects by down-regulating the PI(3)K-Akt survival signaling pathway in addition to inhibiting topoisomerase I.

Tissue distribution and antitumor activity of topotecan delivered by intracerebral clysis in a rat glioma model.

Abstract: OBJECTIVE Intracerebral clysis is a drug delivery technique that depends on convection-enhanced microinfusion to achieve therapeutic drug levels within the brain. In this study, brain tumor-bearing rats were treated with topotecan delivered systemically and by the intracerebral clysis method. Our objective was to determine the efficacy and tissue distribution of topotecan delivered by intracerebral clysis. METHODS The C6/Wistar rat glioma model was used after a thymidine incorporation assay determined topotecan sensitivity of C6 cells in vitro. Long-term survival of animals provided objective measurements of efficacy; records of animal weight during treatment and neurological status served to approximate toxicity. Topotecan tissue penetration was measured in samples of ex vivo tumor and surrounding brain tissue with high-pressure liquid chromatography. RESULTS Dose escalation demonstrated significant sensitivity of C6 glioma cells to topotecan (median lethal dose, 0.19 micromol/L). Eleven of 12 rats bearing established intracerebral C6 glioma and receiving topotecan by intracerebral clysis survived beyond the end point of 120 days; no untreated control or systemically treated animal survived beyond 26 days (n = 18; P < 0.005). Histopathological assessment of animals demonstrated significant tumor masses in the brains of intraperitoneally treated animals and untreated control animals. In contrast, no residual tumor was found in the brains of intracerebral clysis groups. Animal weights during treatment were markedly reduced by intraperitoneal dosing (n = 6) but not by low-dose intracerebral clysis (32 microg/kg/d for 5 d; n = 6). None of the low-dose intracerebral clysis-treated animals demonstrated neurological toxicity, and one high-dose intracerebral clysis-treated animal (160 microg/kg/d for 2 d; n = 6) died during follow-up. Topotecan was detected well beyond the boundaries of the tumor and even in the contralateral hemisphere in animals treated with intracerebral clysis. CONCLUSION Topotecan delivered by the intracerebral clysis method is effective for treatment of brain tumors in the rat glioma model. These studies provide compelling justification for further preclinical testing to formally evaluate toxicity and efficacy with variable dosing schedules.

Complete Regression of Xenografted Human Carcinomas by Camptothecin Analogue-Carboxymethyl Dextran Conjugate (T-0128)

Abstract: Clinically available camptothecins (CPTs), such as irinotecan (CPT-11) and topotecan, represent one of the most promising classes of antitumor agents, despite their toxicity. To improve their pharmacological profiles, a new macromolecular prodrug, denoted T-0128, was synthesized. This prodrug is a novel CPT analogue (T-2513)-carboxymethyl (CM) dextran conjugate via a triglycine spacer, with a molecular weight of Mr 130,000. This study was designed to test the concept that the rational design of a CPT-polymer conjugate would increase the efficacy of the parent drug. The in vivo antitumor study against Walker-256 carcinoma demonstrated that T-0128 was 10 times as active as T-2513, supporting this concept. Additionally, comparative efficacy studies of T-0128, T-2513, CPT-11, and topotecan were performed using a panel of human tumor xenografts in nude mice, showing the advantage of T-0128 over these CPTs. The maximal tolerated doses (MTDs) of T-0128, T-2513, and CPT-11 were comparable. Even a single i.v. injection of T-0128 at 6 mg/kg (based on the amount of T-2513 bound to CM dextran) induced complete regression of MX-1 mammary carcinoma. T-0128 at 10 mg/kg weekly for 3 weeks (one-tenth of its MTD) cured LX-1 lung carcinoma. Also, T-0128 below its MTD consistently cured or regressed St-4 gastric and HT-29 colorectal tumor xenografts that are highly refractory to CPTs. These demonstrate the broad range of therapeutic doses achieved with T-0128. Pharmacokinetic studies were performed to correlate the efficacy results obtained for T-0128 with plasma and tissue drug concentrations using Walker-256 tumor-bearing rats. Results showed that after i.v. administration of T-0128, the conjugate continued to circulate at a high concentration for an extended period, resulting in tumor accumulation. In the tumor, the sustained release of T-2513 occurred. In contrast, T-2513 disappeared rapidly from the body. The significant increases in the amount and exposure time of released T-2513 in the tumor explain well the enhanced efficacy of T-0128. In conclusion, this study indicated that T-0128 improved the potency of T-2513, demonstrating the proof of the above concept.

Phase I Pharmacologic Study of Oral Topotecan and Intravenous Cisplatin: Sequence-Dependent Hematologic Side Effects

Abstract: PURPOSE: In in vitro studies, synergism and sequence-dependent effects were reported for the combination of topotecan and cisplatin. Recently, an oral formulation of topotecan became available. This phase I study was performed to assess the feasibility of the combination of oral topotecan and cisplatin, the pharmacokinetic interaction, and sequence-dependent effects. PATIENTS AND METHODS: Topotecan was administered orally (PO) daily for 5 days in escalating doses and cisplatin was given intravenously (IV) at a fixed dose of 75 mg/m2 either before topotecan administration on day 1 (sequence CT) or after topotecan administration on day 5 (sequence TC) once every 3 weeks. Patients were treated in a randomized cross-over design. RESULTS: Forty-nine patients were entered onto the study; one patient was not eligible. Sequence CT induced significantly more severe myelosuppression than did sequence TC, and the maximum-tolerated dosage of topotecan in sequence CT was 1.25 mg/m2/d × 5. In sequence TC, the maximum-t...

Thymidine kinase gene therapy with concomitant topotecan chemotherapy for recurrent ovarian cancer.

Abstract: Introduction: Patients with recurrent ovarian cancer were treated with a replication-deficient recombinant adenovirus containing the herpes simplex virus thymidine kinase gene administered intraperitoneally (i.p.) followed by administration of an anti-herpetic prodrug and topotecan. Materials and Methods: A total of 10 patients with stage IIIc epithelial ovarian cancer underwent secondary debulking to ≤0.5 cm residual tumor. Patients with normal i.p. flow received i.p. delivery of adenovirus. Two patients each were treated on dose level 1 (2 × 1010 vector particles (VP)), dose level 2 (2 × 1011 VP), and dose level 3 (2 × 1012 VP); four patients were treated on dose level 4 (2 × 1013 VP). Acyclovir and topotecan were started 24 hours after vector delivery. Results: No patient treated at any dose level incurred unanticipated toxic effects, and all side effects resolved. The most common adverse event was myelosuppression: grade 3 or 4 thrombocytopenia with grade 2–4 anemia in three patients and grade 3 or 4 neutropenia in eight patients. Three patients developed thrombocytosis and three patients had a mild elevation of serum glutamic pyruvic transaminase/alanine aminotransferase. Temperature elevations that were not associated with detectable infection occurred in two patients. Discussion: I.p. delivery of adenoviral vector with concomitant topotecan chemotherapy was well tolerated without significant lasting toxicities. Side effects were independent of the dose of adenoviral vector.

Pilot study of topotecan and high-dose cyclophosphamide for resistant pediatric solid tumors.

Abstract: Background The recommended dosages of topotecan and cyclophosphamide in combination for prior-treated patients—3.75 mg/m2 and 1,250 mg/m2 in children, 5 mg/m2 and 600 mg/m2 in adults, respectively—are well below those of each agent when used singly. We tested the hypothesis that much higher dosing would meet critical goals of salvage therapy: antitumor effect and a lack of toxicity to key organs, so as not to preclude subsequent consolidative treatments needed for cure. Procedure Patients with resistant pediatric solid tumors received cyclophosphamide 4,200 mg/m2 by 48 hr infusion, and topotecan 6 mg/m2 by 72 hr infusion (HD-Cy/Topo). Mesna and granulocyte colony-stimulating factor were used. Cycles were repeated when neutrophil counts were >1,000/uL and platelet counts were >75,000/uL. Results Twenty-eight patients, aged 2 to 33 years (median, 14), received one (n = 4), two (n = 15), or ≥3 (n = 9) cycles of HD-Cy/Topo. All patients had previously received ≥6 cycles of other therapy, high-dose alkylator-based chemotherapy, and/or etoposide- and doxorubicin-containing regimens. HD-Cy/Topo was given in an outpatient setting. Profound myelosuppression was the major toxicity, but retreatment was possible by day 28, and preliminary results with peripheral blood stem cell collections showed a sparing effect on hemopoietic stem cells. Mucositis was uncommon. After HD-Cy/Topo, cardiac, renal, hepatic, and pulmonary function remained within the normal range. Partial or minor responses were noted in neuroblastoma, desmoplastic small round-cell tumor, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. Conclusions Its antitumor potential and limited toxicity make HD-Cy/Topo an attractive choice for inclusion in aggressive salvage programs aimed at achieving cures of resistant tumors. It may also merit incorporation into frontline treatment protocols. Med. Pediatr. Oncol. 35:468–474, 2000. © 2000 Wiley-Liss, Inc.

Sensitivity to TRAIL/APO-2L-mediated apoptosis in human renal cell carcinomas and its enhancement by topotecan.

Abstract: TRAIL (APO-2L) is a newly identified member of the TNF family and induces apoptosis in cancer cells without affecting most non-neoplastic cells, both in vitro and in vivo. Our study focused on the expression and function of TRAIL and its receptors in renal cell carcinoma (RCC) cell lines of all major histological types. Here, we demonstrate that all RCC cell lines express TRAIL as well as the death-inducing receptors TRAIL-R1 (DR4) and TRAIL-R2 (Killer/DR5). Exposure to TRAIL induced apoptosis in 10 of 16 RCC cell lines. Remarkably, five of six TRAIL-resistant RCC cell lines exhibited high levels of TRAIL expression. Topotecan, a novel topoisomerase I inhibitor, induced upregulation of TRAIL-R2 as well as downregulation of TRAIL. Neutralization of TRAIL with recombinant soluble TRAIL-R1-Fc and TRAIL-R2-Fc failed to inhibit topotecan-induced apoptosis indicating that topotecan-induced cell death can occur in a TRAIL-independent fashion. However, exposure to topotecan resulted in an enhancement of TRAIL-induced apoptosis in all primarily TRAIL-resistant RCC cell lines. This synergistic effect of cotreatment with Topotecan and TRAIL may provide the basis for a new therapeutic approach to induce apoptosis in otherwise unresponsive RCC. Cell Death and Differentiation (2000) 7, 1127–1136.

Population Pharmacokinetic Model for Topotecan Derived From Phase I Clinical Trials

Abstract: PURPOSE: To characterize the pharmacokinetics of topotecan in a population model that would identify patient variables or covariates that appreciably impacted on its disposition. PATIENTS AND METHODS: All data were collected from 82 patients entered in four different phase I trials that were previously reported as separate studies from 1992 to 1996. All patients received topotecan as a 30-minute constant-rate infusion on a daily-times-five schedule and were selected for this study because their daily dose did not exceed 2.0 mg/m2. Among the 82 patients were 30 patients classified as having renal insufficiency and 13 patients with hepatic dysfunction. The population pharmacokinetic model was built in sequential manner, starting with a covariate-free model and progressing to a covariate model with the aid of generalized additive modeling. RESULTS: A linear two-compartment model characterized total topotecan plasma concentrations (n = 899). Four primary pharmacokinetic parameters (total clearance, volume of ...

Phase II feasibility study of sequential couplets of Cisplatin/Topotecan followed by paclitaxel/cisplatin as primary treatment for advanced epithelial ovarian cancer: a National Cancer Institute of Canada Clinical Trials Group Study.

Abstract: PURPOSE: Despite the improved results in advanced ovarian cancer achieved with the addition of paclitaxel to frontline therapy, there remains room for improvement. One approach is to add new agents such as topotecan. Because myelosuppression limits the delivery of topotecan with paclitaxel/cisplatin in a three-drug combination, we explored giving sequential couplets of cisplatin/topotecan followed by paclitaxel/cisplatin. PATIENTS AND METHODS: Forty-four patients with residual epithelial ovarian carcinoma after primary surgery were studied. Cisplatin 50 mg/m2 on day 1 and topotecan 0.75 mg/m2 on days 1 through 5 were administered at 21-day intervals for four cycles, followed by interval debulking surgery (if optimal debulking was not achieved with primary surgery), and then paclitaxel 135 mg/m2 over 24 hours on day 1 and cisplatin 75 mg/m2 on day 2 at 21-day intervals for four cycles. RESULTS: Such sequential couplets are feasible. Myelotoxicity was the major toxic effect, but it was of short duration. Th...

Growth inhibitory effect of a new camptothecin analog, DX-8951f, on various drug-resistant sublines including BCRP-mediated camptothecin derivative-resistant variants derived from the human lung cancer cell line PC-6.

Abstract: DX-8951f, a new water-soluble camptothecin (CPT) derivative, has been reported to show potent antitumor effects against various tumors in vitro and in vivo We further evaluated the cytotoxic effect of DX-8951f against eight drug-resistant sublines derived by stepwise exposure of human oat cell carcinoma PC-6 to various drugs In paclitaxel-, adriamycin-, vincristine- and etoposide-resistant cells, overexpression of P-glycoprotein (P-gp) and a correlative reduction in drug accumulation and typical drug-sensitivity pattern were confirmed The etoposide-resistant line with the highest P-gp level was cross-resistant also to SN-38, CPT-11 and topotecan (TPT), but not to 9-aminocamptothecin (9-AC), CPT and DX-8951f SN-38- and CPT-11-resistant cells, of which topoisomerase I activities and levels were similar to those of the parent cells, showed cross-resistance clearly to TPT, 9-AC and mitoxantrone, but hardly to DX-8951f In these two resistant sublines, the intracellular topotecan level was significantly lower than that in parental PC-6 and the reduced accumulation was found to be mediated by breast cancer resistant protein (BCRP) The cisplatin-resistant variant, which had a 2-fold increase in glutathione content, showed no cross-resistance and the 5-fluorouracil-resistant variant, which had a 50% decrease in glutathione content, exhibited collateral sensitivity to most of the other anticancer agents including DX-8951f We concluded that DX-8951f showed a potent cytotoxic effect on various types of drug-resistant cells

Inter- and intrapatient variability in oral topotecan pharmacokinetics: implications for body-surface area dosage regimens

Abstract: Anticancer drugs still are dosed based on the bodysurface area (BSA) of the individual patient, although the BSA is not the main predictor of the clearance for the majority of drugs. The relevance of BSA-based dosing has not been evaluated for topotecan yet. A retrospective pharmacological analysis was performed of kinetic data from four clinical Phase I studies in which topotecan was administered p.o. as a single agent combined with data from a combination study of topotecan and cisplatin. A strong correlation (r 5 0.91) was found between the area under the plasma concentration time curve of the lactone and carboxylate forms of topotecan by plotting 326 data sets obtained from 112 patients receiving oral topotecan at dose levels ranging from 0.15‐2.70 mg/m 2 . The intrapatient variability, studied in 47 patients sampled for 3 or more days, for the apparent lactone clearance, ranged from 7.4 ‐ 69% (mean, 24 6 13%; median, 20%). The interpatient variabilities in the lactone clearance, calculated with the data of all studied patients, expressed in liter/h/m 2 and in liter/h were 38% and 42%, respectively. In view of the relatively high inter- and intrapatient variabilities in topotecan clearance, in contrast to a variability of only 12% in the BSA of the studied patients, no advantage of BSA-based dosing was found over fixed dose regimens.

Clinical use of topoisomerase I inhibitors in anticancer treatment.

Abstract: The camptothecin analogs topotecan and irinotecan have shown to be among the most effective anticancer agents and, as S-phase specific agents, their antitumor effect is maximized when they are administered in protracted schedules. The documented activity as single agents in many adult and pediatric malignancies has been followed by their use in combination with other anticancer agents. These studies have shown promising results, and have placed topotecan and irinotecan in the first line treatment for some malignancies. However, studies to better determine the optimal schedules and sequence of combinations are needed.

Optimum chemotherapy for ovarian cancer.

Abstract: A series of prospective randomized trials recently have defined the new standard of care for chemotherapy patients with ovarian cancer. The current preferred regimen consists of carboplatin (dosed to an area-under-the-curve [AUC] of 5.0-7.5) plus paclitaxel (175 mg/m2-3 h infusion). This is an outpatient regimen that does not require growth factor support and six cycles are administered on a 21-day schedule. There is no evidence that any type of additional therapy impacts upon survival, including additional cycles of the same chemotherapy or switching to an alternative intravenous chemotherapy, high-dose chemotherapy with hematologic support, intraperitoneal chemotherapy, or whole abdominal radiation. The majority of patients will achieve a clinical complete remission with the regimen although the relapse rate remains high. Current trials are exploring new schedules of drug delivery as well as new combinations which include new agents such as gemcitabine and topotecan.

Phase II trial of topotecan in patients with advanced, persistent, or recurrent uterine leiomyosarcomas: a Gynecologic Oncology Group Study.

Abstract: From October 1995 to March 1997, a phase II trial of topotecan was carried out in chemotherapy-naive women with advanced, persistent, or recurrent uterine leiomyosarcomas. Thirty-six patients were entered. Median age was 53 years. Performance status was 0 (50%) in 18, 1 (36%) in 13, and 2 (14%) in 5. Most patients, 33 (92%), had undergone prior surgery, and 8 (22%) prior radiation therapy. Topotecan, 1.5 mg/m2. was administered intravenously daily for 5 days, every 3 weeks, until progression of disease or adverse affects prohibited further therapy. Patients received 1 to 13 courses with a median of 3 courses. The most frequent grade 4 adverse effects were neutropenia in 28 (78%), leukopenia in 8 (22%), thrombocytopenia in 3 (8%), and anemia in 3 (8%). Complete response was seen in 1 (3%), partial response in 3 (8%), stable disease in 12 (33%), and increasing tumor in 20 (56%). Thus topotecan at this dose and schedule does not appear to have major activity in uterine leiomyosarcomas.

Cross-resistance of topoisomerase I and II inhibitors in neuroblastoma cell lines

Abstract: Purpose: We have previously shown that neuroblastoma cell lines established from patients after intensive chemotherapy show sustained resistance to various drugs and especially high resistance to etoposide (up to 51 times higher than a clinically achievable level). To determine whether topoisomerase I inhibitors (topotecan and CPT-11) are effective against etoposide-resistant neuroblastomas, we studied the response to topotecan and the active metabolite of CPT-11 (SN-38) in 19 cell lines with a spectrum of sensitivities to etoposide. Materials and methods: The panel included cell lines established at diagnosis and after disease progression either during induction chemotherapy or after myeloablative therapy supported with bone marrow transplantation. Cytotoxicities of topotecan, SN-38, and etoposide were determined using a microplate digital image microscopy (DIMSCAN) assay with a 4-log dynamic range. Results: All six etoposide-resistant cell lines were resistant to topotecan and SN-38 (resistance defined as LC90 higher then clinically achievable levels for the drug). Significant cross-resistance by Pearson's correlation analysis (r ≥ 0.6) occurred between topotecan + etoposide, topotecan + SN-38, and etoposide + SN-38. Conclusions: Topotecan and CPT-11 do not have significant activity against most etoposide-resistant neuroblastoma cell lines and this suggests that agents other than topoisomerase inhibitors should be explored for the treatment of recurrent neuroblastomas.

Intensive chemotherapy for patients with high-risk myelodysplastic syndrome.

Abstract: Standard antileukemic chemotherapy induces complete remission in approximately half of patients with high-risk (HR) myelodysplastic syndrome (MDS). Intensification of induction therapy by the use of intermediate- or high-dose cytosine arabinoside in combination with fludarabine, idarubicin, or topotecan seemingly improved complete response (CR) rates, particularly in patients with poor prognosis karyotypes. The various high-intensity regimens appear to be comparable in inducing CR, although some are better tolerated with low mortality even in advanced-age populations with MDS. The encouraging early results with new agents, eg, topoisomerase inhibitors (topotecan) and hypomethylating agents (5-azacytidine), have been disappointing because long-term follow-up has shown continuous relapses. Regardless of the intensity of chemotherapy, remissions are short, even with continuation of intensive postremission therapy. Long-term disease-free survival remains dismal. In a large population with HR MDS treated with high-dose chemotherapy, only 5% of patients were alive at 3 years, and a majority of survivors were the younger patients with diploid karyotype refractory anemia with excess blasts in transformation. Further intensification of either induction chemotherapy or postremission therapy is unlikely to improve results with current drug combinations. With these results at hand, the role of intensive chemotherapy in the management of MDS remains controversial. Because CR status is associated with clinical benefits and possibly better survival, induction of CR should remain an important aim for HR MDS. The intensive combination chemotherapy may be integrated as an initial part of the management of HR MDS, as an alternative for patients not eligible for allogeneic bone marrow transplantation (BMT). Regimens with low early mortality, eg, topotecan plus intermediate dose Ara-C, could also be used to reduce tumor load prior to allogeneic BMT. Induction of CR should be attempted with the most effective and best tolerated regimens, particularly, but not only, in younger patients with good performance status regardless of karyotype. Postremission therapy remains a major challenge. It should involve either allogeneic BMT or investigational approaches to eliminate or control the minimal residual disease with different mechanisms In elderly patients, allogeneic "minitransplant" is an investigational alternative seeking to exploit graft-versus-tumor reaction. New agents, such as farnesyl transferase inhibitors (ras inhibitors), drug-antibody conjugates (Myelotarg), thalidomide, arsenic trioxide, maintenance chemotherapy with hypomethylating agents, or oral topoisomerase inhibitors along with agents modulating factors affecting growth and differentiation, should be explored to maintain remission with minimal compromise of quality of life. Although prognostic scoring systems such as the new International Prognostic Scoring System (IPSS) do not predict for initial response, IPSS continues to predict survival in patients treated with high-dose chemotherapy. Although activity of new agents could be rapidly assessed in single-arm pilot studies, the final merit of high-dose chemotherapy could be assessed only in well-designed randomized trials with patients assigned according to risk-based classification and evaluated for response by generally accepted and standardized criteria.

Homocamptothecin, an E-Ring-modified Camptothecin, Exerts More Potent Antiproliferative Activity than Other Topoisomerase I Inhibitors in Human Colon Cancers Obtained from Surgery and Maintained in Vitro under Histotypical Culture Conditions

Abstract: Topoisomerase I (Topo I) is overexpressed in cancer colon tissues compared with normal colon tissues. Several anti-Topo I inhibitors are already successfully used in the clinic. We illustrate here the antiproliferative activity of a new class of Topo I inhibitors, i.e., E-ring-modified camptothecins with enhanced lactone stability (L. Lesueur-Ginot et al., Cancer Res., 59: 2939-2943, 1999). Forty-three human colon cancers were obtained from surgical resection and maintained under organotypical culture conditions for 48 h. Cell proliferation was assessed in these ex vivo tumor tissue cultures by tritiated thymidine autoradiography. As a validation of the methodology, we first analyzed in our model the antiproliferative activity of two clinically active topoisomerase II (Topo II) inhibitors, Adriamycin and etoposide, which are not active for colon cancers; and three Topo I inhibitors, camptothecin (CPT) and two clinically active compounds (especially for colon cancers), i.e., topotecan and the active metabolite of irinothecan, SN-38. We then compared the antiproliferative activity of CPT, topotecan, and SN-38 against those of two investigational E-ring-modified camptothecins, i.e., BN80245 and BN80915. Three concentrations (1, 10, and 100 nM) were studied for each compound. The results indicate that the three Topo I inhibitors used as references, i.e., CPT, irinothecan, and SN-38, were much more active than the two Topo II inhibitors, i.e., Adriamycin and etoposide, with SN-38 being the most efficient. The two investigational compounds BN80245 and BN80915 exerted higher antiproliferative activity than the three anti-Topo I reference compounds, with the highest activity observed for BN80915.

Therapeutic advances in small cell lung cancer.

Abstract: Small cell lung cancer (SCLC) is characterised by neuroendocrine differentiation, early metastatic potential and initial responsiveness to cytotoxic therapy. Unfortunately, despite recent therapeutic advances, most patients relapse and the overall five-year survival rate is only 5%. Standard treatment of SCLC consists of platinum-based combination chemotherapy, with thoracic irradiation added for patients with limited-stage disease. Several newer chemotherapeutic drugs have recently been shown to have significant activity in patients with untreated or relapsed SCLC. These agents include: the topoisomerase I inhibitors, topotecan and irinotecan; the taxanes, paclitaxel and docetaxel; the pyrimidine analogue, gemcitabine; and the vinca alkaloid, vinorelbine. Recent advances in our understanding of the molecular events involved in the pathogenesis and progression of SCLC have led to the identification of a variety of potential targets for novel therapeutic interventions. Strategies aimed at inhibiting the myriad of growth factor pathways that control the proliferation of SCLC cells, include: broad spectrum neuropeptide antagonists (e.g., substance P analogues); growth factor/receptor-specific inhibitors (e.g., anti-GRP monoclonal antibodies, bradykinin antagonist dimers); and a variety of selective protein kinase inhibitors. The importance of cell death pathways in carcinogenesis and treatment-resistance has led to several novel strategies targeting apoptotic mediators, such as bcl-2, that are frequently dysregulated in SCLC (e.g., bcl-2 antisense). Our current challenges are to further refine these promising therapeutic strategies, efficiently evaluate their activity in the clinical setting and integrate them into more effective treatment regimens to improve the overall prognosis of patients with SCLC.

Population pharmacokinetics of topotecan: intraindividual variability in total drug.

Abstract: The inter- and intraindividual variabilities in topotecan clearance (CL) were explored using a population pharmacokinetic approach. Total (lactone + hydroxy acid) topotecan plasma concentrations were obtained in 31 women with metastatic epithelial ovarian cancer treated by the 30-min intravenous infusion on 5 subsequent days. The data corresponding to three occasions (days 1 and 5 of cycle 1, and day 1 of cycle 2), were analyzed using the nonlinear mixed effect model program. A large interindividual variability was observed, with CL varying from 9.1 to 42.5 l per hour (mean 21.0). Topotecan CL was related to serum creatinine level, and age. A close relationship was also observed between topotecan CL and creatinine clearance. Intraindividual variability both within cycle 1 and between the two first cycles was limited, with a mean variation of −2 ± 17%, and +5 ± 20%, respectively. A limited sampling strategy using Bayesian estimation based on two samples (5 min before the end of the 30-min infusion, and 4 h after the end of infusion) was developed. The results of this study combine relationships between topotecan pharmacokinetic parameters and patient covariates that may be useful for a priori dose adjustment, and convenient sampling procedure that can be used for further studies and drug monitoring.

Cyclophosphamide, Ara-C and Topotecan (CAT) for Patients With Refractory or Relapsed Acute Leukemia

Abstract: Topotecan is a topoisomerase I inhibitor with significant activity in patients with myelodysplastic syndrome and chronic myelomonocytic leukemia. Pre-clinical data suggest a synergistic activity with DNA damaging agents such as cyclophosphamide, where topotecan might prevent the repair of cyclophosphamide-induced DNA damage. We thus designed a combination including cyclophosphamide 500 mg/m2 every 12 hours given on days 1 to 3; topotecan 1.25 mg/m2/day by continuous infusion on days 2 to 6, and cytosine arabinoside (ara-C) 2 g/m2 over 4 hours daily for 5 days on days 2 to 6 (CAT). Sixty six (63 evaluable) patients were treated. Fifty two patients had refractory (n=12) or relapsed (n=40) acute myelogenous leukemia (AML), and eleven had acute lymphocytic leukemia (ALL) (refractory n=3, relapsed n=8); their median age was 57 years (range, 18 to 79 years). Eleven patients (17%) achieved a complete remission (CR), and two patients (3%) had a hematologic improvement (HI; met all criteria for CR except for platelets < 100x10(9)/L), for an overall response rate of 20%. Responses occurred in 12 of 52 AML patients (23%), including 10 CR (19%) and 2 HI (4%), and in 1 of 11 patients with ALL (9%). Myelosuppression was universal; there were 23 episodes of pneumonia or sepsis and 18 episodes of fever of unknown origin complicating 74 courses of CAT. Non-hematologic toxicity was mostly gastrointestinal, including nausea, vomiting, diarrhea and mucositis, but was severe in only 8%. In summary, the CAT regimen is well tolerated and has significant anti-leukemia activity which warrants further investigation.