Phase I and pharmacologic study of the combination of paclitaxel, cisplatin, and topotecan administered intravenously every 21 days as first-line therapy in patients with advanced ovarian cancer.
(1/578)
PURPOSE: To evaluate the feasibility of administering topotecan in combination with paclitaxel and cisplatin without and with granulocyte colony-stimulating factor (G-CSF) support as first-line chemotherapy in women with incompletely resected stage III and stage IV ovarian carcinoma. PATIENTS AND METHODS: Starting doses were paclitaxel 110 mg/m2 administered over 24 hours (day 1), followed by cisplatin 50 mg/m2 over 3 hours (day 2) and topotecan 0.3 mg/m2/d over 30 minutes for 5 consecutive days (days 2 to 6). Treatment was repeated every 3 weeks. After encountering dose-limiting toxicities (DLTs) without G-CSF support, the maximum-tolerated dose was defined as 5 microg/kg of G-CSF subcutaneously starting on day 6. RESULTS: Twenty-one patients received a total of 116 courses at four different dose levels. The DLT was neutropenia. At the first dose level, all six patients experienced grade 4 myelosuppression. G-CSF support permitted further dose escalation of cisplatin and topotecan. Nonhematologic toxicities, primarily fatigue, nausea/vomiting, and neurosensory neuropathy, were observed but were generally mild. Of 15 patients assessable for response, nine had a complete response, four achieved a partial response, and two had stable disease. CONCLUSION: Neutropenia was the DLT of this combination of paclitaxel, cisplatin, and topotecan. The recommended phase II dose is paclitaxel 110 mg/m2 (day 1), followed by cisplatin 75 mg/m2 (day 2) and topotecan 0.3 mg/m2/d (days 2 to 6) with G-CSF support repeated every 3 weeks. (+info)
Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer.
(2/578)
PURPOSE: Topotecan and cyclophosphamide, doxorubicin, and vincristine (CAV) were evaluated in a randomized, multicenter study of patients with small-cell lung cancer (SCLC) who had relapsed at least 60 days after completion of first-line therapy. PATIENTS AND METHODS: Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 107) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, and vincristine 2 mg) infused on day 1 every 21 days (n = 104). Eligibility included the following: bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of less than or equal to 2, and adequate marrow, liver, and renal function. Response was confirmed by blinded independent radiologic review. RESULTS: Response rate was 26 of 107 patients (24.3%) treated with topotecan and 19 of 104 patients (18.3%) treated with CAV (P = .285). Median times to progression were 13.3 weeks (topotecan) and 12.3 weeks (CAV) (P = .552). Median survival was 25.0 weeks for topotecan and 24.7 weeks for CAV (P = .795). The proportion of patients who experienced symptom improvement was greater in the topotecan group than in the CAV group for four of eight symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue, as well as interference with daily activity (P< or =.043). Grade 4 neutropenia occurred in 37.8% of topotecan courses versus 51.4% of CAV courses (P<.001). Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with topotecan, occurring in 9.8% and 17.7% of topotecan courses versus 1.4% and 7.2% of CAV courses, respectively (P<.001 for both). Nonhematologic toxicities were generally grade 1 to 2 for both regimens. CONCLUSION: Topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms. (+info)
Detection of poly(ADP-ribose) polymerase cleavage in response to treatment with topoisomerase I inhibitors: a potential surrogate end point to assess treatment effectiveness.
(3/578)
Cleavage of poly(ADP-ribose) polymerase (PARP) by caspases is a prominent characteristic of apoptosis or programmed cell death shown to be induced by topoisomerase (Topo) inhibitors. Because Topo I inhibitors have been shown to be effective in the treatment of some patients with colon cancer, we considered the possibility of using PARP cleavage as an early predictor of responsiveness to this class of agents. We show cleavage of PARP in response to treatment with Topo I inhibitors in colon cancer both in vitro and in vivo: (a) in vitro in SW480, HCT116, VACO5, VACO6, VACO8, VACO411, VACO425, and VACO451 human colon cancer cell lines treated with topotecan (TPT) or CPT-11; (b) in vivo in SW480, VACO451, and VRC5 colon cancer xenografts grown in athymic mice treated with TPT or CPT-11; and (c) in vivo in colon cancer samples from patients undergoing a Phase II clinical trial with CPT-11. Our results show a strong correlation between percentage of PARP cleavage and percentage of acridine orange-positive cells in colon cancer cell lines treated with 0.1 microM TPT for 24 and 48 h, confirming that PARP cleavage is a useful marker for programmed cell death in colon cancer cell lines. Results from experiments performed on colon cancer xenografts also show an association between PARP cleavage and response to treatment with TPT or CPT-11. The increase of PARP cleavage in xenografts and in clinical samples corresponding to treatment with Topo I inhibitors suggests that this procedure may have early predictive value to assess effectiveness of treatment. These results provide the basis for determining the validity of using PARP cleavage as an early marker of chemotherapeutic effectiveness in human samples. (+info)
Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225.
(4/578)
Epidermal growth factor (EGF)-related proteins such as transforming growth factor alpha (TGF-alpha) control cancer cell growth through autocrine and paracrine pathways. Overexpression of TGF-alpha and/or its receptor (EGFR) has been associated with a more aggressive disease and a poor prognosis. The blockade of EGFR activation has been proposed as a target for anticancer therapy. Monoclonal antibody (MAb) C225 is an anti-EGFR humanized chimeric mouse MAb that is presently in Phase II clinical trials in cancer patients. Previous studies have suggested the potentiation of the antitumor activity of certain cytotoxic drugs, such as cisplatin and doxorubicin, in human cancer cell lines by treatment with anti-EGFR antibodies. We have evaluated in human ovarian, breast, and colon cancer cell lines, which express functional EGFR, the antiproliferative activity of MAb C225 in combination with topotecan, a cytotoxic drug that specifically inhibits topoisomerase I and that has shown antitumor activity in these malignancies. A dose-dependent supraadditive increase of growth inhibition in vitro was observed when cancer cells were treated with topotecan and MAb C225 in a sequential schedule. In this respect, the cooperativity quotient, defined as the ratio between the actual growth inhibition obtained by treatment with topotecan followed by MAb C225 and the sum of the growth inhibition achieved by each agent, ranged from 1.2 to 3, depending on drug concentration and cancer cell line. Treatment with MAb C225 also markedly enhanced apoptotic cell death induced by topotecan. For example, in GEO colon cancer cells, 5 nM topotecan, followed by 0.5 microg/ml MAb C225, induced apoptosis in 45% cells as compared with untreated cells (6%) or to 5 nM topotecan-treated cells (22%). Treatment of mice bearing established human GEO colon cancer xenografts with topotecan or with MAb C225 determined a transient inhibition of tumor growth because GEO tumors resumed the growth rate of untreated tumors at the end of the treatment period. In contrast, an almost complete tumor regression was observed in all mice treated with the two agents in combination. This determined a prolonged life span of the mice that was significantly different as compared with controls (P < 0.001), to MAb C225-treated group (P < 0.001), or to the topotecan-treated group (P < 0.001). All mice of the topotecan plus MAb C225 group were the only animals alive 14 weeks after tumor cell injection. Furthermore, 20% of mice in this group were still alive after 19 weeks. The combined treatment with MAb C225 and topotecan was well tolerated by mice with no signs of acute or delayed toxicity. These results provide a rationale for the evaluation of the anticancer activity of the combination of topoisomerase I inhibitors and anti-EGFR blocking MAbs in clinical trials. (+info)
Extending the platinum-free interval in recurrent ovarian cancer: the role of topotecan in second-line chemotherapy.
(5/578)
Although the combination of platinum and paclitaxel offers effective chemotherapy for advanced ovarian cancer, the majority of women will eventually relapse with development of drug-resistant disease. Topotecan is the most extensively studied agent currently available for management of recurrent ovarian cancer and has been approved by the FDA for that particular indication. Early use of topotecan offers an effective and tolerable strategy that can prolong the platinum-free interval and optimize subsequent retreatment with platinum. (+info)
Cisplatin-topotecan-paclitaxel weekly administration with G-CSF support for ovarian and small-cell lung cancer patients: a dose-finding study.
(6/578)
PURPOSE: Paclitaxel (PTX) and topotecan (TPT) have shown promising antitumor activity in both ovarian cancer (OC) and small-cell lung cancer (SCLC) patients. This phase I study was aimed at determining the maximum tolerable dose (MTD) of TPT given weekly over 30 min in combination with fixed doses of cisplatin (CDDP) and (PTX), and with G-CSF support. PATIENTS AND METHODS: Forty-four patients with OC (19) or SCLC (25), either chemo-naive (20) or pretreated (24) received CDDP 40 mg/m2, PTX 85 mg/m2 (one-hour infusion) and escalating TPT doses (starting from 0.75 mg/m2) in a 30-min infusion in weekly administration. Filgrastim 5 mg/kg was administered on days 3 to 5 of each week. RESULTS: Eight different dose levels were tested for a total of 295 delivered cycles. The dose escalation was interrupted at the TPT dose of 2.50 mg/m2. No toxic deaths occurred in this study. Grade 3 to 4 neutropenia, thrombocytopenia, and anemia occurred in 15 patients (36 cycles), seven patients (15 cycles), and four patients (five cycles), respectively. Severe vomiting and diarrhoea occurred in seven and four patients. Peripheral neuropathy was recorded in 11 patients (42 cycles), but it was never severe. An overall 11 of 19 (58%) OC and 11 of 25 (44%) SCLC patients obtained objective responses. Eight patients showed complete responses (three OC and three SCLC). Among the 20 chemo-naive patients, 9 of 11 (82%) OC and seven of nine (78%) SCLC responded. CONCLUSIONS: The CDDP/TPT/PTX weekly administration with filgrastim support represents a well-tolerated and active therapeutic approach in both chemo-naive and pretreated OC and SCLC patients. A weekly dose of TPT of 2.25 mg/m2 is recommended for the phase II study. (+info)
Vitronectin, a glioma-derived extracellular matrix protein, protects tumor cells from apoptotic death.
(7/578)
Vitronectin (VN) is an extracellular matrix (ECM) protein, the synthesis of which in vivo by glioma cells correlates with tumor grade. Although the role of VN as a permissive substrate for glioma migration has been well characterized, its role in conferring a survival advantage for tumor cells has not been addressed previously. By using an in vitro assay of DNA fragmentation as a quantitative measure of apoptotic cell death, we sought to determine whether the sensitivity of two human glioma cell lines (D54 and U251) to drug-induced apoptosis could be inhibited by VN. As well, the extent to which apoptosis could be inhibited was correlated with the levels of the Bcl-2 family of proteins that are known to modulate apoptosis and chemoresistance. Results of the study were: (a) VN coatings, in a dose-dependent manner, inhibited topoisomerase (Topo)-induced apoptosis by up to 50% (optimal coating density, 500 ng/cm2); in contrast, fibronectin (FN), an ECM protein present in abundance in the brain, demonstrated no protection; (b) in a dose-response study, VN clearly conferred a survival advantage (LD50 of Topo: on VN, 120 ng/ml; on FN, 35 ng/ml); (c) the protective effect of VN was not due to enhanced cell adhesion or alterations in the cell cycle distribution; (d) both of the classic integrin receptors that bind VN (alpha(v)beta3, alpha(v)beta5) were capable of mediating this protective effect, because ligation of either of the two classic integrins conferred chemoresistance to Topo; and (e) chemoresistance observed with VN was associated with an increase in expression of two antiapoptotic proteins, Bcl-2 and Bcl-X(L), with a consequent increase in the ratios for Bcl-2:Bax and Bcl-X(L):Bax. VN, an ECM protein preferentially expressed at the tumor-brain interface in vivo, may confer a survival advantage to glioma cells at the advancing tumor margin and may thus, in part, underlie the high level of tumor recurrence at this interface. (+info)
Effect of loss of DNA mismatch repair on development of topotecan-, gemcitabine-, and paclitaxel-resistant variants after exposure to cisplatin.
(8/578)
Loss of DNA mismatch repair (MMR) causes genomic instability by markedly increasing the frequency of sporadic mutations in both coding and noncoding sequences. Little is known about how loss of MMR affects sensitivity to the mutagenic effect of chemotherapeutic agents. We wanted to determine how loss of MMR affects the ability of cisplatin, a known mutagen, to generate human tumor cell variants resistant to other drugs with which cisplatin is commonly combined in treatment regimens. We compared the ability of cisplatin to produce variants resistant to topotecan, gemcitabine, and paclitaxel in two pairs of MMR-proficient and -deficient cells that included sublines of the human colon carcinoma cell line HCT-116 and sublines of the human endometrial adenocarcinoma cell line HEC59. Cells were exposed to increasing concentrations of cisplatin for 1 h, and the surviving population was tested for the frequency of variants resistant to these single molecular target drugs 10 days later. The frequency of variants increased linearly with cisplatin concentration for all three drugs. Cisplatin was 2.6 +/- 0.3- (S.D.), 3.6 +/- 0.9-, and 2.3 +/- 0.1-fold more potent at producing topotecan-, gemcitabine-, and paclitaxel-resistant variants in the MMR-deficient than in the MMR-proficient HCT116 cells (P <.05 for all). Cisplatin was 1.4 +/- 0.3- and 1.4 +/- 0.4-fold more potent at generating topotecan- and gemcitabine-resistant variants in MMR-deficient HEC59 cells than in MMR-proficient HEC59+ch2 cells. Cisplatin was not more potent in generating paclitaxel-resistant variants in the MMR-deficient HEC59 cells. Spontaneous rates of generation of cells resistant to these three drugs were also measured in the HCT116 sublines. MMR-deficient HCT116 cells exhibited rates of generation of resistant variants that were 1.94- and 1.51-fold higher (P <.05) than those in the MMR-proficient cells for topotecan and gemcitabine, respectively; loss of MMR had no effect on the rate of generation of variants resistant to paclitaxel. We conclude that the loss of MMR increases the ability of cisplatin to generate variants resistant to topotecan, gemcitabine, and possibly paclitaxel and that MMR also plays a role in controlling the spontaneous rate of generation of variants resistant to topotecan and gemcitabine. (+info)