Showing papers on "Topotecan published in 1995"
TL;DR: Results indicate that low-dose protracted schedules of daily administration of these topoisomerase I inhibitors is either equi-effective or more efficacious than more intense shorter schedules of administration reported previously.
Abstract: The efficacy of protracted schedules of therapy of the topoisomerase I inhibitors 9-dimethylaminomethyl-10-hydroxycamptothecin (topotecan) and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (irinotecan; CPT-11) were evaluated against a panel of 21 human tumor xenografts derived from adult and pediatric malignancies. Tumors included eight colon adenocarcinomas, representing an intrinsically chemorefractory malignancy, six lines derived from childhood rhabdomyosarcoma (three embryonal, three alveolar) representing a chemoresponsive histiotype, sublines of rhabdomyosarcomas selected in vivo for resistance to vincristine and melphalan, and three pediatric brain tmors. All tumors were grown at the subcutaneous site. Topotecan was administered by oral gavage 5 days per week for 12 consecutive weeks. The maximum tolerated dose (MTD) was 1.5 mg/kg per dose. Irinotecan was given by i.v. administration daily for 5 days each week for 2 weeks [(d×5)2] (one cycle of therapy), repeated every 21 days. The MTD for three cycles was 10 mg/kg per dose. Treatment was started against advanced tumors. Topotecan caused a high frequency of objective regressions in one of eight colon tumor lines, whereas irinotecan caused complete regressions (CR) of all tumors in three colon lines and a high frequency of CRs in three additional lines. Both drugs demonstrated similar activity against rhabdomyosarcoma xenografts. Topotecan caused CR of all tumors in four of six lines, and irinotecan in five of six lines evaluated. Both agents retained full activity against tumors selected for primary resistance to vincristine, but only irinotecan retained activity against a tumor selected for primary resistance to melphalan. Both agents demonstrated good activity against brain tumor xenografts with irinotecan causing CR in two of three lines and topotecan inducing CR in one of three lines. Results indicate that low-dose protracted schedules of daily administration of these topoisomerase I inhibitors is either equi-effective or more efficacious than more intense shorter schedules of administration reported previously.
380 citations
TL;DR: Because of manageable toxicity and encouraging activity against solid tumours, topoisomerase I-active drugs offer promise in the clinical management of human tumours.
Abstract: The nuclear enzymes topoisomerase I and II are critical for DNA function and cell survival, and recent studies have identified these enzymes as cellular targets for several clinically active anticancer drugs. Topoisomerase II inhibitors (anthracyclines, epipodophyllotoxins, etc.) are active against several types of tumours. However, treatment with these drugs often results in the development of the multi-drug resistance. Because topoisomerase II-active drugs have several different modes of action, different mechanisms of resistance, including decreased activation and increased detoxification by glutathione-dependent enzymes, have also been implicated. Unlike topoisomerase II, topoisomerase I is not a cell cycle-dependent enzyme and, therefore, it is a more desirable cellular target for anticancer drug development. Topoisomerase I inhibitors, such as camptothecin and its derivatives, have shown significant activity against a broad range of tumours and, in general, are not substrates for either the multi-drug-resistance P-170 glycoprotein or the multi-drug-resistance-associated protein. Because of manageable toxicity and encouraging activity against solid tumours, topoisomerase I-active drugs offer promise in the clinical management of human tumours.
162 citations
TL;DR: In human tumor cell cytotoxicity assays, compounds 6 and 7 demonstrated potent antitumor activity against ovarian, ovarian with upregulated MDRp-glycoprotein (SKVLB), melanoma, breast, breast (T47D), and colon (HT29) with IC50's ranging from 0.5 to 102 nM.
Abstract: The synthesis and antitumor activities of the novel water soluble camptothecin derivatives 7-[(4-methylpiperazino)methyl]-10,11-(methylenedioxy)-(20S)-campto thecin trifluoroacetate (6) and 7-[(4-methylpiperazino)methyl]-10,11-(ethylenedioxy)-(20S)-camptot hecin trifluoroacetate (7) are described. The solubilities of compounds 6 and 7 were measured to be 4.5 and 5.8 mg/mL, respectively, in pH 5 acetate buffer in contrast to < 0.003 mg/mL for camptothecin in the same buffer. In the purified topoisomerase I cleavable complex enzyme assay, compounds 6 and 7 demonstrated potent inhibition of topoisomerase I with IC50's of 300 and 416 nM, respectively, in comparison to 679 nM for camptothecin and 1028 nM for topotecan. In human tumor cell cytotoxicity assays, compounds 6 and 7 demonstrated potent antitumor activity against ovarian (SKOV3), ovarian with upregulated MDRp-glycoprotein (SKVLB), melanoma (LOX), breast (T47D), and colon (HT29) with IC50's ranging from 0.5 to 102 nM. Compounds 6 and 7 induced tumor regressions in the HT29 human colon tumor xenograft model and demonstrated similar rank order of potency compared to in vitro assay results.
148 citations
TL;DR: A water‐soluble and non‐pro‐drug analog of camptothecin, DX‐8951f, is synthesized and shows both high in vitro potency against a series of 32 malignant cell lines and significant topoisomerase I inhibition, suggesting that DX‐ 8951f has a high antitumor activity and is a potential therapeutic agent.
Abstract: CPT-11, a semisynthetic derivative of camptothecin, exhibited strong antitumor activity against lymphoma, lung cancer, colorectal cancer, gastric cancer, ovarian cancer, and cervical cancer. CPT-11 is a pro-drug that is converted to an active metabolite, SN-38, in vivo by enzymes such as carboxylesterase. We synthesized a water-soluble and non-pro-drug analog of camptothecin, DX-8951f. It showed both high in vitro potency against a series of 32 malignant cell lines and significant topoisomerase I inhibition. The anti-proliferative activity of DX-8951f, as indicated by the mean GI50 value, was about 6 and 28 times greater than that of SN-38 or SK&F 10486-A (Topotecan), respectively. These three derivatives of camptothecin showed similar patterns of differential response among 32 cell lines, that is, their spectra of in vitro cytotoxicity were almost the same. The antitumor activity of three doses of DX-8951f administered i.v. at 4-day intervals against human gastric adenocarcinoma SC-6 xenografts was greater than that of CPT-11 or SK&F 10486-A. Moreover, it overcame P-glycoprotein-mediated multi-drug resistance. These data suggest that DX-8951f has a high antitumor activity and is a potential therapeutic agent.
142 citations
TL;DR: Topotecan was therefore found to significantly penetrate into the CSF in humans and the pharmacokinetic model presented may be useful in the design of clinical studies of topOTecan to treat CNS tumors.
Abstract: The purpose of this study was to describe the cerebrospinal fluid (CSF) penetration of topotecan in humans, to generate a pharmacokinetic model to simultaneously describe topotecan lactone and total concentrations in the plasma and CSF, and to characterize the CSF and plasma pharmacokinetics of topotecan administered as a continuous infusion (CI). Plasma and CSF samples were collected from 17 patients receiving 5.5 or 7.5 mg/m2 per day as a 24-h CI (5 patients, 7 courses), or 0.5 to 1.25 mg/m2 per day as a 72-h CI (12 patients, 12 courses). CSF samples were obtained from either a ventricular reservoir (VR) or a lumbar puncture (LP). Topotecan lactone and total (lactone plus hydroxy acid) concentrations were determined by HPLC and fluorescence detection. Using MAP-Bayesian modelling, a three-compartment model was fitted simultaneously to topotecan lactone and total concentrations in the plasma and CSF. The penetration of topotecan into the CSF was determined from the ratio of the CSF to the plasma area under the concentration-time curve. The median CSF ventricular lactone concentrations, obtained prior to the end of infusion (EOI), were 0.86, 1.4, 0.73, 5.3 and 4.6 ng/ml for patients receiving 0.5, 1.0, 1.25, 5.5, and 7.5 mg/m2 per day, respectively. EOI CSF lumbar lactone concentrations measured in three patients were 0.44, 1.1, and 1.7 ng/ml for topotecan doses of 1.0, 5.5, and 7.5 mg/m2 per day, respectively. In two patients receiving 1.25 mg/m2 per day, EOI CSF concentrations were obtained simultaneously from a VR and LP; the lumbar lactone concentrations were 30% and 49% lower than the ventricular concentrations. During a 24-h and a 72-h CI, the median CSF penetration of topotecan lactone was 0.29 (range 0.10 to 0.59) and 0.42 (range 0.11 to 0.86), respectively. A three-compartment model adequately described topotecan lactone and total concentrations in the plasma and CSF. Topotecan was therefore found to significantly penetrate into the CSF in humans. The pharmacokinetic model presented may be useful in the design of clinical studies of topotecan to treat CNS tumors.
137 citations
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TL;DR: The ICE bioassay can evaluate the effects of topoisomerase I inhibitors on target tissues; thus, it may valuable in predicting response to these drugs.
Abstract: As part of a Phase II clinical trial of topotecan, DNA breakage in vivo was measured by detecting covalent topoisomerase/DNA intermediates in peripheral blood. The ICE ( in vivo complex of enzyme) bioassay was used to assess topotecan activity in the peripheral blood of patients before, during, and after infusion therapy. The results can be summarized as: ( a ) ICE bioassay is a specific, antibody-based assay for topoisomerase I-mediated DNA damage. Topoisomerase I/DNA complex formation can be monitored unamibugously in the absence of topotecan to establish a basal level of endogenous enzyme action on DNA; ( b ) infusion of topotecan significantly stimulated formation of covalent enzyme/DNA complexes. Complexes were detected within 5 min postinfusion and increased over the course of a 30-min treatment; ( c ) after termination of infusion, complex formation decreased by 3–4-fold within 30 min, showing that cleavage complexes quickly reseal after drug withdrawal; and ( d ) formation of complexes varied widely between patients. The ICE bioassay can evaluate the effects of topoisomerase I inhibitors on target tissues; thus, it may valuable in predicting response to these drugs.
105 citations
Journal Article•
TL;DR: It is reported that this mitoxantrone-resistant human breast carcinoma cell line is highly cross-resistant to the camptothecin analogues topotecan, and DNA relaxation activities were equal in both cell lines and inhibited to the same extent by topOTecan and campthecin.
Abstract: We have previously described a mitoxantrone-resistant human breast carcinoma cell line, MCF7/MX, in which resistance was associated with a defect in the energy-dependent accumulation of mitoxantrone in the absence of P-glycoprotein overexpression (M. Nakagawa et al., Cancer Res. 52: 6175-6181, 1992). We now report that this cell line is highly cross-resistant to the camptothecin analogues topotecan (180-fold), 9-aminocamptothecin (120-fold), CPT-11 (56-fold), and SN38 (101-fold), but is only mildly cross-resistant to the parent compound camptothecin (3.2-fold) and 10,11-methylenedioxy-camptothecin (2.9-fold). Topotecan accumulation was decreased in MCF7/MX cells compared to parental MCF7/WT cells, and there was a corresponding reduction in topotecan-mediated stimulation of the enzyme/DNA complex formation in MCF7/MX cells compared to MCF7/WT cells. No overexpression of the multidrug resistance-associated protein was detected compared to parental MCF7/WT cells. Furthermore, both sensitive MCF7/WT and mitoxantrone-resistant MCF7/MX cells contain equal amounts of DNA topoisomerase I protein, and DNA relaxation activities were equal in both cell lines and inhibited to the same extent by topotecan and camptothecin. Thus, these results suggest a novel mechanism of resistance to topoisomerase I inhibitors in cancer cells.
97 citations
TL;DR: The biophysical factors underlying the markedly improved bloodstream stability and cytotoxic activity of topotecan relative to camptothecin are elucidated.
Abstract: Topotecan, a semisynthetic water-soluble analogue of camptothecin, is the first topoisomerase I targeting anticancer agent to enter comparative phase III clinical trials. Here we elucidate the biophysical factors underlying the markedly improved bloodstream stability and cytotoxic activity of topotecan relative to camptothecin. Each agent contains an alpha-hydroxy-delta-lactone ring that hydrolyzes under physiological pH to yield a biologically-inactive carboxylate form. In human plasma, camptothecin lactone converts rapidly and completely to its carboxylate form due to a 200-fold binding preference by serum albumin (HSA) for the latter [Mi, Z., & Burke, T.G. (1994) Biochemistry 33, 10540-12545]. Time-resolved fluorescence anisotropy measurements reveal that neither topotecan lactone nor carboxylate associates with HSA, thereby resulting in a significantly higher level of lactone stability in plasma for topotecan (t1/2 = 23.1 min, percent lactone at equilibrium of 17.6) relative to camptothecin (t1/2 = 10.6 min, percent lactone at equilibrium of < 0.2). Moreover, studies with HL-60 human promyelocytic leukemia cells reveal that a physiologically-relevant level (40 mg/mL) of HSA dramatically attenuates the cytotoxic activity of camptothecin in excess of 2600-fold (for a 72 h exposure, the IC50 value of 1.5 nM in the absence of HSA increased to 4 microM in the presence of HSA). The activities of other clinically relevant anticancer analogues, 9-aminocamptothecin and SN-38, were also strongly modulated by the presence of 40 mg/mL HSA. In marked contrast, the presence of HSA effected no change on the cytotoxic activity of topotecan (IC50 = 12 nM both in the absence and in presence of HSA).(ABSTRACT TRUNCATED AT 250 WORDS)
95 citations
Journal Article•
TL;DR: 9-AC is an active antitumor agent and may be administered safely as a 72-h infusion in patients with cancer, and alternate schedules should be evaluated given the dramatic preclinical activity seen with more prolonged administrations.
Abstract: Camptothecins are the only available antitumor agents which target the nuclear enzyme topoisomerase I. 9-Aminocamptothecin (9-AC) is a water-insoluble derivative of camptothecin which has demonstrated impressive antitumor activity in preclinical models. While two other water-soluble derivatives, CPT-11 and topotecan, have successfully completed Phase I and Phase II testing, biochemical and tissue culture studies suggest that camptothecin analogues differ in characteristics which may be important in determining antitumor activity. We performed a Phase I trial of 9-AC to determine the pharmacokinetics, dose-limiting toxicity, and maximum tolerated dose of this agent when administered as a 72-h continuous i.v. infusion. Thirty-one patients with resistant solid cancers received 5-60 microgram/m2/h 9-AC for 72 h, repeated at 3-week intervals. The drug was administered in a vehicle containing dimethylacetamide, polyethylene glycol, and phosphoric acid. Blood samples were collected and the lactone (closed ring) form of 9-AC was quantitated. The maximum tolerated dose of 9-AC was determined to be 45 microgram/m2/h. Dose-limiting toxicity consisted of neutropenia. Thrombocytopenia was also prominent. There were no significant nonhematological toxicities. Minimal responses were seen in patients with gastric, colon, and non-small cell lung cancer. Although significant interpatient variation in plasma 9-AC lactone levels was observed, pooled data were fit to a two-compartment model, with a terminal half-life of 36 h. Analyses of topoisomerase protein levels in peripheral blood cells indicated decreases in topoisomerase I accompanied by increases in topoisomerase II in two of three patients. 9-AC is an active antitumor agent and may be administered safely as a 72-h infusion in patients with cancer. Although Phase II trials with a 72-h infusion of 9-AC are warranted, alternate schedules should be evaluated given the dramatic preclinical activity seen with more prolonged administrations.
94 citations
Journal Article•
TL;DR: Tumor cell cytotoxicity assays using 5 separate cell lines demonstrated that both GI compounds were 5-10 times more potent than topotecan, although by comparison all three topoisomerase I inhibitors were unaffected by the multidrug resistance P-glycoprotein.
Abstract: The development of camptothecin-like compounds as inhibitors of topoisomerase I for the treatment of resistant tumors has generated clinical excitement in this new class of drugs. We have developed two novel water-soluble camptothecin analogues which are specific inhibitors of topoisomerase I and are potent cytotoxins with significant antitumor activity. We added water-solubilizing groups off position 7 in the B ring of either 10,11-ethylenedioxy- or 10,11-methylenedioxy-20(S)-camptothecin. These water-soluble camptothecin analogues were demonstrated to be nanamolar inhibitors of the topoisomerase I enzyme in the cleavable complex assay. The compounds, GI147211 [7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)-camptothecin], and GI149893 [7-(4-methylpiperazinomethylene)-10,11-methylenedioxy-20(S)-camptothecin], were compared to topotecan, a known water-soluble inhibitor of topoisomerase I. Both GI compounds were found to be slightly more potent than topolecan as inhibitors of topoisomerase I in the cleavable complex assay and were 1.5–2 times more soluble. Tumor cell cytotoxicity assays using 5 separate cell lines demonstrated that both GI compounds were 5–10 times more potent than topotecan, although by comparison all three topoisomerase I inhibitors were unaffected by the multidrug resistance P-glycoprotein. The antitumor activity of all three topoisomerase I inhibitors was compared concomitantly in two human colon xenograft models. In both models, GI147211 and GI149893 were able to induce regression of established HT-29 and SW-48 colon tumors by as much as 60%. The antitumor activity of both compounds were also demonstrated in the MX-1 and PC-3 xenografts. Microscopic examination of selected tissues indicated that drug-induced toxicity was primarily limited to the gastrointestinal tract and was comparable among the three compounds. Further clinical development of this class of compounds is ongoing.
92 citations
TL;DR: There were linear relationships between the dose, the area under the plasma concentration versus time curve (AUC) of topotecan and its metabolite, the total AUC, peak plasma lactone concentrations, and the time period that the topotican concentrations remained above 10 nM.
Abstract: Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ringopened hydroxy acid, is essential for this activity. The open form predominates at physiological pH. We performed a pharmacokinetic, study as part of a phase I study in patients with various types of solid tumors, where topotecan was administered in a 30-min infusion daily on 5 consecutive days every 3 weeks. The plasma kinetics of topotecan could be described best using an open two-compartment model with t1/2(α) and t1/2(β) of 8.1 (range 0.3 to 40.7) min and 132 (range 49 to 286) min, respectively. The plasma concentration-time profiles of the metabolite, however, could be described using a one-compartment model with t1/2(formation) of 29.0 (range 5.6–99.5) min and t1/2 (elimination of 123.2 (range 32–265) min, respectively. The lactone was the predominate form during the first hour from the start of infusion, but was rapidly converted into its ring-opened structure. The elimination rate of topotecan was independent of the dose. There were linear relationships between the dose (mg m−2 day−1), the area under the plasma concentration versus time curve (AUC) of topotecan and its metabolite, the total AUC, peak plasma lactone concentrations, and the time period that the topotecan concentrations remained above 10 nM. Different models were used to correlate pharmacokinetic and pharmacodynamic parameters. The percentage decrease in absolute neutrophil count (ANC) was related to these parameters and plots were well fitted by linear and sigmoidal Emax models.
TL;DR: It is concluded that paclitaxel can be given at clinically relevant doses in combination with topotecan and filgrastim, and the recommended dose for phase II studies is pac litaxel 230 mg/m2 on day 1 and topOTecan 1.0 mg/ m2/day for 5 days with filGrastim 5 micrograms/kg on days 6 to 14.
Abstract: PURPOSETo define the dose-limiting toxicities (DLTs) and the recommended phase II doses of paclitaxel combined with topotecan, without and with filgrastim support.PATIENTS AND METHODSPatients with advanced solid tumors and a maximum of one prior chemotherapy regimen for metastatic disease were eligible if they had a performance status of 0 to 1 and normal renal, hepatic, and bone marrow function. Prior treatment with taxanes or comptothecin analogs, and prior pelvic irradiation were not allowed. Patients with a history of cardiac disease or on medications known to affect cardiac conduction were excluded. The dose of topotecan was fixed at 1.0 mg/m2/d for 5 days. The dose of paclitaxel was escalated until the maximum-tolerated dose (MTD), without and with filgrastim 5 micrograms/kg subcutaneously (SC) on days 6 to 14, was reached. Paclitaxel was administered over 3 hours on day 1 before topotecan. Treatment cycles were repeated every 21 days.RESULTSOf 46 patients entered, 45 were assessable for toxicity an...
TL;DR: The recommended dose for phase II studies is 8.4 mg/m2 when administered as a 24-hour infusion, which is well tolerated, and further studies will be necessary to account for the putative nonlinear behavior of the drug.
Abstract: PURPOSETo determine the maximum-tolerable dose (MTD) and to investigate the pharmacokinetics and pharmacodynamics of topotecan in a phase I study. Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. Broad preclinical activity rationalized further clinical evaluation.PATIENTS AND METHODSIn this phase I trial, topotecan was administered by 24-hour continuous infusion every 21 days to patients with solid malignant tumors.RESULTSA total of 25 eligible patients, of whom 22 were pretreated, entered the study. They received the following dosages of topotecan: 2.5, 3.75, 5.60, 8.4, and 10.5 mg/m2 by 24-hour infusion. Reversible leukopenia and thrombocytopenia were dose-limiting, with mild anemia occurring regularly. Other toxicities, such as alopecia, mucositis, nausea, and vomiting were sporadic and mild. Responses were not observed. However, eight patients had stable disease. The plasma concentration-time curves were not compat...
TL;DR: Although conventional cytotoxic chemotherapy agents used alone or in combination have demonstrated activity in MF/SS, there are no studies that clearly demonstrate improvement in survival of treated patients.
Abstract: Although conventional cytotoxic chemotherapy agents used alone or in combination have demonstrated activity in MF/SS, there are no studies that clearly demonstrate improvement in survival of treated patients. Newer compounds worthy of further clinical investigation in these patients include temazolamide, an alkylating agent with activity in brain neoplasms, the taxanes, and topoisomerase inhibitors, including topotecan and CPT-11. In addition, the combination of cytotoxic chemotherapies with biologic modalities, such as targeted toxins and immunomodulatory agents, has yet to be explored.
Journal Article•
TL;DR: The results demonstrate that topoisomerase I and II active agents introduce mutations characterized by gene deletions and rearrangements, whereas spontaneous mutations and those induced by alkylating agents appeared to be more characteristically associated with point mutations.
Abstract: Topoisomerase I-directed agents are now in Phase I and II clinical trials and show great promise as potentially important agents for cancer chemotherapy. Because of their mechanism of action they may also be potential mutagens; however, their mutagenicity and oncogenicity still remain to be elucidated. We have previously shown that VP-16, a topoisomerase II-directed agent, induces sister chromatid exchanges and gene deletions and/or rearrangements in vitro. These observations may account for both the cytotoxic effects of topoisomerase II-directed agents as well as their recently reported leukemonogenic potential. To evaluate the potential mutagenicity of topoisomerase I-directed drugs, we measured mutant frequencies at the hypoxanthine phosphoribosyl transferase locus of the V79 Chinese hamster fibroblast cell line treated with the topoisomerase I-directed drugs camptothecin and topotecan, and compared these results with mutant frequency obtained with the topoisomerase II-directed drug VP-16 and an alkylating agent, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). All of these drugs showed a dose-dependent increase in mutant frequency at the hypoxanthine phosphoribosyl transferase locus. At a dose producing approximately 30% survival, VP-16, camptothecin, and topotecan induced mutant frequencies of 11.3 x 10(-6), 4.9 x 10(-6), and 2.7 x 10(-6), respectively, whereas the spontaneous mutant frequency at this locus was 0.3 x 10(-6). In contrast, the alkylating agent MNNG produced a mutant frequency of 562 x 10(-6) at 26% survival dose. The molar mutagenic potencies, expressed as mutant frequency/mol-h exposure, for VP-16, camptothecin, topotecan, and MNNG at approximately 30% survival dose were 0.9, 8.2, 2.3, and 56.8, respectively. On Southern blot analysis after EcoRI, PstI, or HindIII digestion, 6 of 12 independent thioguanine-resistant mutants induced by topotecan showed gene deletions or rearrangements. In contrast, five of five independent spontaneous mutants and six of six independent mutants induced by MNNG demonstrated the same restriction pattern as the parental V79 cells. These results indicate that the mutant frequency and the mutagenic potential of topoisomerase I and II active agents are quantitatively similar. The results further demonstrate that topoisomerase I and II active agents introduce mutations characterized by gene deletions and rearrangements, whereas spontaneous mutations and those induced by alkylating agents appeared to be more characteristically associated with point mutations. Thus, clinical use of the topoisomerase I and II active agents is expected to cause similar mutagenic effects that could potentially lead to secondary malignancies.
TL;DR: A series of analogs based on a novel template, 11-aza-(20S)-camptothecin, were obtained from total synthesis and tested as potential anticancer drugs in the topoisomerase I enzyme cleavable complex assay and proved to be effective in whole cell cytotoxicity assays.
Abstract: A series of analogs based on a novel template, 11-aza-(20S)-camptothecin, were obtained from total synthesis and tested as potential anticancer drugs in the topoisomerase I enzyme cleavable complex assay. The parent compound 11-aza-(20S)-camptothecin (8) was derived from a Friedlander condensation between the known aminopyridine derivative 3-(3-amino-4-picolylidene)-p-toluidine and optically active tricyclic ketone 7. Compound 8 had activity approximately twice that of (20S)-camptothecin in the calf thymus topoisomerase I cleavable complex assay. Compounds were prepared wherein the 11-aza nitrogen atom was quaternized as either the corresponding N-oxide or methyl iodide. Compounds with quaternized N-11 showed improved water solubility and were equipotent to the clinically investigated camptothecin analog topotecan in the cleavable complex assay. These compounds were evaluated in vivo in nude mice bearing HT-29 human colon carcinoma xenografts. The analog 11-aza-(20S)-camptothecin 11-N-oxide was found to significantly retard tumor growth when compared to untreated controls. Finally, 7,10-disubstituted 11-azacamptothecin analogs were synthesized using Pd(0) coupling reactions of 10-bromo-7-alkyl-11-aza-(20S)-camptothecins 19 and 20, which in turn were available from a Friedlander condensation of the novel bromopyridine derivatives 17a and 17b with 7. Among the 10-substituted series, a number of analogs displayed extremely high in vitro potency against topoisomerase I and improved aqueous solubility. A significant number of the compounds were found to be active in whole cell cytotoxicity assays and several were evaluated in nude mice bearing the HT-29 tumor xenografts. The most effective of these proved to be (S)-11-aza-7-ethyl-10-(aminohydroximinomethyl)camptothecin trifluoracetic acid salt (27), a potent topoisomerase I inhibitor which demonstrated excellent efficacy in both short term and in extended in vivo assays. A comparison between in vitro enzyme data and in vivo data from nude mouse studies in other compounds in this series revealed a poor overall correlation between topoisomerase inhibition in vitro and antitumor efficacy in vivo.
TL;DR: It is shown that topotecan stabilizes topoisomerase I/DNA cleavable complexes in radiation-resistant human B-lineage acute lymphoblastic leukemia (ALL) cells, causes rapid apoptotic cell death despite high-level expression of bcl-2 protein, and inhibits ALL cell in vitro clonogenic growth in a dose-dependent fashion.
TL;DR: In this paper, the cerebrospinal fluid (CSF) pharmacokinetics of topotecan were studied in a nonhuman primate model following intraventricular administration of 0.1 mg.
Abstract: The cerebrospinal fluid (CSF) pharmacokinetics of topotecan were studied in a nonhuman primate model following intraventricular administration of 0.1 mg. Lactone and total drug concentrations were measured using a reverse-phase HPLC method with fluorescence detection. The mean peak concentrations of lactone and total drug in ventricular CSF were 83±18 μM and 88±25 μM, respectively. CSF drug elimination of the lactone was bi-exponential with a terminal half-life of 1.3 h. The mean clearance from ventricular CSF was 0.075 ml/min for the lactone and 0.043 ml/min for total drug. The ventricular CSF drug exposure (AUC) to lactone was 450-fold greater following intraventricular administration of 0.1 mg topotecan than after systemic intravenous administration of a 40-fold higher dose (10 mg/m2). Peak lumbar concentrations (n=1), which occurred 2 h after intraventricular drug administration, were 0.98 μM and 2.95 μM for the lactone and total drug, respectively. A transient CSF pleocytosis was observed in one animal following intraventricular topotecan administration and in one animal following intralumbar topotecan administration. No other acute or chronic neurologic or systemic toxicities were observed following a single intraventricular dose or weekly (×4) intralumbar topotecan. Compared with systemic topotecan, intrathecal administration provided a significant pharmacokinetic advantage in terms of CSF drug exposure and did not produce any significant neurotoxicity in a nonhuman primate model. Intrathecal topotecan should be evaluated clinically as a potential alternative therapy for refractory meningeal tumors.
TL;DR: Topotecan (TPT), a hydrophilic derivative of camptothecin, is currently undergoing phase II clinical trials in small-cell lung cancer (SCLC) as mentioned in this paper.
Abstract: Camptothecins are DNA topoisomerase I-directed anti-tumour drugs with a novel mechanism of action. Topotecan (TPT), a hydrophilic derivative of camptothecin, is currently undergoing phase II clinical trials in small-cell lung cancer (SCLC). Human SCLC OC-NYH cells were made more than 6-fold resistant to topotecan by stepwise drug exposure and resistance was stable for 70 passages without drug. NYH/TPT cells had half the topoisomerase I level and activity of wild-type cells. However, no difference in camptothecin or topotecan inhibition of topoisomerase I-mediated DNA relaxation was found, indicating that the enzyme itself was unchanged in the resistant cell. In NYH/TPT cells, topoisomerase II alpha and beta levels were increased approximately 2-fold. Accordingly, the topoisomerase II-directed drug etoposide (VP-16) induced an increased number of DNA single-strand breaks in NYH/TPT cells. However, sensitivity to different topoisomerase II-targeting agents in NYH/TPT cells varied from increased to decreased, indicating a role for as yet unidentified factors acting on the pathway to cell death after topoisomerase II-induced DNA damage has occurred. Of 20 anti-cancer agents tested, only hydroxyurea showed marked collateral hypersensitivity in NYH/TPT cells.
TL;DR: Topotecan administered as a daily-times-five regimen has only minor activity as a single-agent therapy in colorectal cancer.
TL;DR: Topotecan, in this dose and schedule, has low activity in adult soft tissue sarcoma.
TL;DR: Clinical development has produced new agents, including chloroquinoxaline sulfonamide, docetaxel, edatrexate, gemcitabine, irinotecan, topotecans, and vinorelbine, which hold promise for more successful treatment of this lethal disease.
Journal Article•
TL;DR: It is reported that LIP-TPT was three- to fourfold more effective than free TPT in stabilizing covalent topoisomerase I-DNA intermediates inside tumor cells.
Abstract: Topotecan, a topoisomerase I poison and water-soluble derivative of camptothecin, has shown promise in treating solid tumors; however, the drug is unstable under physiological conditions and converts to an inactive form within 30 minutes. Encapsulating topotecan in liposomes (LIP-TPT) minimizes inactivation. The efficacy of LIP-TPT was examined with a novel in vivo bioassay called ICE for In vivo Complexes of Enzyme. This bioassay uses antibodies to probe DNA for the presence of topoisomerase I covalent complexes and thereby allows direct quantification of topoisomerase I driven DNA adducts in living cells. We report that LIP-TPT was three- to fourfold more effective than free TPT in stabilizing covalent topoisomerase I-DNA intermediates inside tumor cells. These findings reveal that liposomal wrapping permitted effective delivery of camptothecin derivatives to active enzyme in the nucleus of the cell.
TL;DR: Even with lower peak cone and AUC's, oral T maintains it's biologic activity.
TL;DR: Topotecan given on a 5 day, short infusion schedule, demonstrated limited activity in pancreatic carcinoma with minimal toxicity.
Abstract: A phase II trial of topotecan, an inhibitor of topoisomerase I, was conducted in patients with advanced or metastatic adenocarcinoma of the pancreas to determine the activity and toxicity of topotecan. 35 patients, previously untreated with chemotherapy, received topotecan 1.5 mg/ m2/d for five days intravenously and repeated every 21 days. Patients were assessed for response after 3 cycles. Those with either clinical response or stable disease received additional cycles of the drug until toxicity developed or disease progression occurred. Among 30 patients evaluable for response there were no complete responses and 3 partial responses (10%) for a total response rate of 10% (95% confidence interval = 0–20.6%). Stable disease for at least eight weeks was seen in 11 patients (36%). Median survival was 19 weeks (95% confidence interval 11 to 26 weeks). Therapy was generally well tolerated, with reversible granulocytopenia being the most common toxicity. Topotecan given on a 5 day, short infusion schedule, demonstrated limited activity in pancreatic carcinoma with minimal toxicity. Further exploration of topotecan in pancreatic carcinoma using different dosing schedules is warranted.
TL;DR: Intraperitoneal treatment with topotecan appears to be a promising approach in the therapy of refractory ovarian cancer confined to the peritoneal cavity.
Abstract: The therapeutic effects of intraperitoneal topotecan, a water-soluble camptothecin analogue, were investigated in two models of human ovarian carcinoma xenografted intraperitoneally into nude mice: the IGROV-1 tumour, which originated from an untreated patient, and the A2780 tumour, selected for resistance in vitro to cisplatin (A2780DDP). In IGROV-1 tumour-bearing mice, the optimal dose (10 mg kg-1) of topotecan, given intraperitioneally every 4 days for four occasions markedly increased survival time over control mice (300 T/C%) and cured 4/9 mice, and such effects were not achieved by any of the clinically available drugs tested, i.e. cisplatin carboplatin and doxorubicin delivered intraperitonally according to their optimal doses and schedules. In the treatment of A2780DDP tumour-bearing mice, topotecan was very effective since, at dose levels of 6.6 and 10 mg kg-1 every 4 days for four occasions, 15/18 mice survived more than 100 days, and most of them (12/15) were found to be tumour free. The high responsiveness of this tumour to topotecan might be related to the elevated expression of the target enzyme topoisomerase I. From these results, intraperitoneal treatment with topotecan appears to be a promising approach in the therapy of refractory ovarian cancer confined to the peritoneal cavity.
TL;DR: Topotecan administered at this dose and schedule has limited activity in patients with HRPC, and further trials of topo I inibition in HRPC should utilize alternative schedules of topotECan (e.g., prolonged infusion) or other camptothecin analogs with more potent toposomerase I inhibitory activity.
Abstract: Systemic chemotherapy with currently available agents has not improved survival for patients with hormone refractory prostate cancer (HRPC), consequently, the evaluation of new agents is warranted. Topotecan is a specific inhibitor of topoisomerase I with broad antitumor activity in preclinical studies. The purpose of this phase II trial was to determine the objective response rate of topotecan administered as a 30 minute infusion for five consecutive days in men with metastatic HRPC. Thirty-four evaluable patients were treated with topotecan 1.1–1.5 mg/m2 as a 30 minute infusion daily for five days, repeated every three weeks until disease progression or unacceptable toxicity. Response was assessed with a combination of standard solid tumor response criteria and the serum prostate specific antigen (PSA) for patients with bidimensionally measurable disease, and by serial measurements of the PSA in patients with bone only (evaluable) disease.
TL;DR: Fifteen patients with advanced, cisplatin-refractory germ cell tumors (GCT) were treated on a phase II trial with topotecan and none of the 14 evaluable patients achieved a complete or partial response.
Abstract: Fifteen patients with advanced, cisplatin-refractory germ cell tumors (GCT) were treated on a phase II trial with topotecan. None of the 14 evaluable patients achieved a complete or partial response. Myelosuppression was the major toxicity. The median nadir leukocyte count was 1.75 cells/mm3, neutrophil count was 1.55 cells/mm3, hemoglobin was 8.75 gm/dl, and platelet count was 20,500 cells/mm3. Topotecan is not efficacious in the treatment of cisplatin-refractory GCT.
TL;DR: There is a pressing need to find new chemotherapeutic agents for patients with advanced ovarian cancer, and this work highlights the need for new platinum-based chemotherapy agents to be developed.
Abstract: Advanced stage ovarian cancer is the most lethal gynecologic cancer. Despite initial response rates of 60-80% with platinum-based chemotherapy, more than 75% of women with this malignancy die of complications associated with this disease. There is a pressing need to find new chemotherapeutic agents for patients with advanced ovarian cancer. Phase II studies have identified paclitaxel as the most active drug in ovarian cancer since the introduction of cisplatin in the 1970s. Phase III studies will define the role of paclitaxel as initial therapy. Camptothecins (topotecan, CPT-11, 9-amino-camptothecin) inhibit topoisomerase I. CPT-11 and topotecan have shown activity in Phase II trials. Gemcitabine, a pyrimidine antimetabolite, has shown activity in Phase II trials. Other promising drugs (docetaxel, treosulfan) are under investigation. Modulation of drug resistance is being explored in Phase I/II studies. Clinical trials have been initiated with buthionine-sulfoximine, an inhibitor of glutathione biosynthesis, which decreases the ability of resistant cells to inactivate platinum compounds and alkylating agents. Cyclosporin has been shown to increase cisplatin cytotoxicity. Phase I trials have demonstrated the feasibility of combining cyclosporin and cisplatin. Phase II trials of cyclosporin analogs (PSC 833) and paclitaxel in refractory ovarian cancer are ongoing. Promising leads in drug development should provide new therapies for patients with ovarian cancer. Further research in the modulation of drug resistance may identify new mechanisms or strategies with which to prevent the emergence of drug resistance.
Journal Article•
TL;DR: Camptothecin appears to be a poor substrate of P-glycoprotein and its intracellular accumulation is not appreciably reduced in cells expressing the multidrug-resistant phenotype, whereas topotecan and CPT-11 represent two different approaches to the problem of the poor water solubility of campthecin lactone.
Abstract: 20 (S) Camptothecin was discovered in the early 60's as a result of the intensive screening of natural products by the NCI. Camptothecin lactone was poorly water soluble and was administered as the sodium salt in phase I trials. Despite some encouraging responses in early studies, continued evaluation of this compound revealed severe and unpredictable toxicities such as haemorrhagic cystitis and diarrhoea. The reversible opening of the lactone ring of a camptothecin is pH-dependent and yields a ring-opened carboxylate form which has greatly reduced activity in vivo and in vitro. Under physiological conditions, the carboxylate form predominates, but the exact position of this equilibrium in vivo also depends on other factors such as protein-binding and differential metabolism and elimination. The site of action of camptothecin is a complex formed by the nuclear enzyme topoisomerase I and DNA, which represents a novel target for cancer chemotherapy. The principal role of topoisomerase I is the relaxation of DNA required for transcription and replication. The transient covalent complexes formed by the linking of the enzyme and the 3' extremity of a nicked DNA strand are stabilised in the presence of camptothecin and involved in collisions with replication forks. The ensuing arrest of the fork is accompanied by the generation of permanent double-strand breaks which are thought to be responsible for the antiproliferative properties of camptothecin. The acquisition of resistance to camptothecin in cell culture appears, in general, to be due to a reduction in content and activity of topo-isomerase I. Single-point mutations of the gene of the enzyme have been detected in a number of these resistant variants. Camptothecin appears to be a poor substrate of P-glycoprotein and its intracellular accumulation is not appreciably reduced in cells expressing the multidrug-resistant phenotype. Several water soluble and active derivatives of camptothecin have been synthetized of which CPT-11 and topotecan are the most advanced in clinical trials. These compounds represent two different approaches to the problem of the poor water solubility of camptothecin lactone. CPT-11 is a soluble prodrug which is converted in vivo to the highly active SN-38, whereas topotecan itself is water-soluble due to the presence of a tertiary amine substitution which is charged at physiological pH. These two compounds present different pharmacological properties in the clinical setting.