Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topotecan (Hycamtin; SmithKline Beecham Pharmaceuticals, Philadelphia, PA), a camptothecin analog, is a novel and specific inhibitor of the nuclear enzyme topoisomerase I. In preclinical studies, topotecan demonstrated significant in vitro activity in a variety of solid tumor explants derived from colorectal, breast, ovarian, renal cell, non-small cell lung cancer, and gastrointestinal sources. Notable activity was also demonstrated in vivo in a wide range of animal tumor models. A large number of phase I studies with topotecan have been conducted since 1992 in both adults and children with a broad range of refractory malignancies and as many as 14 different dosing schedules. Complete, partial, or minor responses were demonstrated in patients with recurrent or refractory neuroblastoma, non-small cell lung cancer, small cell lung cancer, ovarian cancer, breast cancer, colon cancer, esophageal cancer, renal cell carcinoma, and squamous cell carcinoma. The antitumor activity of topotecan in these phase I evaluations was associated more often with frequent or continuous dosing schedules compared with less frequent or short exposure schedules. Maximum tolerated doses were predominantly dependent on the dosing schedule used. Myelosuppression was the major dose-limiting toxicity across all schedules, and nonhematologic toxicities were generally mild. Data from phase I studies have provided valuable information about antitumor responses, maximum tolerated doses, and dose-limiting toxicities associated with different dosing schedules. Based on this information, there was substantial enthusiasm for further evaluating topotecan in a wide range of cancer patients in phase II studies.
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PMID:Review of phase I clinical studies with topotecan. 942 56

According to the American Cancer Society, 178,100 new cases of lung cancer were predicted in 1997, with an estimated 5-year relative survival rate of 11% to 14%. Non-small cell lung cancer (NSCLC), the most prevalent type of lung cancer, presents an extraordinary challenge to the oncologist, because most patients present with advanced unresectable disease. Cisplatin, one of the most effective single agents against NSCLC, has only moderate antitumor effect and limited impact on survival. Combination regimens also show little increase in survival. In the search for better treatments for NSCLC, new agents with novel mechanisms of action have been explored. In preclinical studies, topotecan (Hycamtin; SmithKline Beecham Pharmaceuticals, Philadelphia, PA), a topoisomerase I inhibitor, demonstrated activity in a variety of animal tumor models. Results from subsequent phase I and phase II clinical trials, summarized here, suggest that topotecan has modest activity against NSCLC and that its role in the treatment of this disease should be evaluated further.
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PMID:Topotecan in the treatment of non-small cell lung cancer. 942 59

Colorectal cancer is the third most common cause of cancer-related death in both men and women. Surgery is the primary form of treatment, with greater than 90% of patients surviving 5 years or more. The remaining patients have metastatic disease, for which treatment options are limited. The fluoropyrimidine, 5-fluorouracil, elicits favorable tumor response rates in patients with metastatic disease, but has little impact on survival. Based on the observation that colorectal tumors have increased levels of topoisomerase I relative to normal tissue, investigations have focused on the camptothecin derivatives, particularly topotecan, as an effective treatment. Topotecan demonstrated antitumor activity in preclinical studies, causing significant growth delay of xenografts in thymectomized, irradiated mice. Clinical studies with topotecan have not yielded as promising results, with response rates of approximately 7% to 10%, but modifications in dosing schedule or combinations with other agents may enhance antitumor activity.
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PMID:Topotecan in advanced colorectal cancer. 942 60

Topotecan, a camptothecin analogue, is a specific inhibitor of topoisomerase I approved for use in the treatment of patients with refractory ovarian carcinoma. The drug's mechanism of action suggests a potential efficacy of drug combinations incorporating DNA-damaging agents. In an attempt better to define a rational basis for drug combination we examined the effect of topotecan on the cytotoxicity and antitumor activity of cisplatin in an ovarian carcinoma system growing in vitro and in vivo as a tumor xenograft. The in vitro cell system included a cisplatin-sensitive cell line, IGROV-1, and a cisplatin-resistant subline, IGROV-1/Pt0.5, which is characterized by p53 mutation and loss of normal function of the wild-type gene of the parental cell line. This cell system was chosen since the cell sensitivity to DNA-damaging agents appears to be dependent on p53 gene status. Cytotoxicity was assessed by the growth inhibition assay using different schedules: (a) a 1-h period of cisplatin exposure followed by a 24-h topotecan treatment and (b) a 1-h period of simultaneous exposure to cisplatin and topotecan. In the case of the sequential schedule, an additive interaction was observed in IGROV-1 and IGROV-1/Pt0.5 cells. When the simultaneous schedule was used, a synergistic interaction, more evident for the cisplatin-sensitive cells, was found. On the basis of these observations at a cellular level, the effect of concomitant administration of the two drugs (i.e., the most favorable schedule) was studied in the IGROV-1 tumor xenograft, which is moderately responsive to cisplatin and topotecan. Suboptimal doses of each drug (with a low dose of topotecan, 5.1 mg/kg) achieved an antitumor effect comparable with or superior to that of the optimal dose of a single treatment (tumor weight inhibition, 60%), thus indicating a pharmacological advantage of the combination over the single treatment. However, an increase in the topotecan dose (7.1 mg/kg) was associated with an evident increase in the toxicity of the combination, thereby suggesting that the drug interaction was not tumor-specific. Although the molecular basis of the drug interaction is not clear, it is likely that inhibition of topoisomerase I affects the ability of cells to repair cisplatin adducts. Such findings may have pharmacological implications since they suggest the potential clinical interest of topoisomerase I inhibitors in combination with cisplatin.
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PMID:In vitro and in vivo interaction between cisplatin and topotecan in ovarian carcinoma systems. 952 34

Monoclonal antibodies (McAb) 19A211, M344 against transitional cell carcinoma (TCC) was used to assay the tumor associated antigens on paraffin-embedded tissue sections of 51 different grades bladder cancer patients with immunohistochemical stain method. The positive rates of 19A211, M344 antigens expression were 82.4% and 88.2% in 17 grade I patients 77.7% and 83.3% in 18 grade II patients, 37.5% and 37.5% in 16 grade III patients. 19A211 and M344 antigens expression in statistical analysis was as follows: 19A211, grade I/grade III, P < 0.01, grade II/grade II, P < 0.05, M344, grade I/grade III, P < 0.01, grade II/grade II, P < 0.05, showed significant differences. Combined use of McAb 19A211 and M344 assay bladder TCC tumor associated antigens, showed that the positive rates of antigen expression in grade I was 100% (17/17), in grade II was 88.8% (16/18), in grade III was 68.8% (11/16). The results indicate that McAb 19A211, M344 were fit to diagnose grade I, II bladder TCC. Using both of two McAb can increase the positive rate in finding superficial bladder TTC.
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PMID:[Monoclonal antibodies against transitional cell carcinoma assay tumor associated antigens in different grades bladder cancer patients]. 959 63

Although small-cell lung cancer (SCLC) represents only 20% of all lung cancer cases in the United States, it is the most lethal subtype. Combination chemotherapy unequivocally offers the best chance for improved survival in SCLC. Either PE (platinum plus etoposide) or CAV (cyclophosphamide, Adriamycin, and vincristine) is a reasonable first-line therapy. Alternating PE with CAV does not appear to be significantly superior to PE or CAV alone. Increasing dose intensity, although sometimes associated with higher response rates, does not appear to significantly improve survival and should not be used outside of a clinical study. Several new agents with novel mechanisms of action show promise in treating SCLC. These include: gemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere), topotecan (Hycamtin), and irinotecan (Camptosar). Given the poor survival and response rates in relapsed patients and the chemoresponsiveness of SCLC, patients with newly diagnosed extensive disease should be encouraged to enroll in phase I or II trials. Thoracic radiotherapy confers a small survival advantage in limited-stage SCLC patients. Although prophylactic cranial irradiation does not significantly improve survival, it does reduce central nervous system (CNS) recurrences with minimal long-term sequelae. Surgery should be considered only for: (1) resection of a solitary pulmonary nodule, which must be followed by adjuvant chemotherapy; and (2) resection of an unresponsive chest tumor, which may harbor a non-small-cell lung cancer component.
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PMID:Small-cell lung cancer: treatment progress and prospects. 959 76

RET proto-oncogene mutation results in a dominant autosomic inherited syndrome (MEN 2) presenting three distinct subtypes: MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC). Detection of RET proto-oncogene mutation is a predictor before clinical or biochemical evidence of the disease is present and leads to preventive thyroid removal since there is no effective treatment for metastases. The aim of the present study was to characterize mutations in the RET proto-oncogene in affected patients and to identify potential carriers in their families. Two families with FMTC (5 and 6 members), 4 with MEN 2A (5, 5, 4 and 3 members) and 2 with MEN 2B (5 and 1 members), were studied. DNA was obtained from blood samples in all patients and from thyroid or from pheonochromocytoma tissues in patients submitted to surgery. PCR amplification was performed using specific primers for exons 10, 11 and 16, followed by direct sequencing. Mutations at codon 634 in exon 11 were found in 16 subjects with FMTC and MEN 2A: TGC --> CGC (cysteine to arginine) in 9 cases, TGC --> TAC (cysteine to tyrosine) in 3, and TGC --> TTC (cysteine to phenilalanine) in 4. A unique mutation of codon 918 in exon 16, ATG --> ACG (methionine to threonine), was found in both MEN 2B affected patients. The mutations detected in DNA from peripheral blood were the same as those present in DNA extracted from tumor material. RET mutations were detected in all affected patients, confirming the diagnosis, and in 10 members of their families. In five of the carriers total thyroidectomy was performed. Anatomopathological study showed C-cells hyperplasia or in-situ microcarcinoma in two children (9 and 12 y) with no clinical signs of diseases and medullary thyroid carcinoma in three adults, who were previously unaware of the presence of thyroid nodules. The early detection of RET mutation followed by total thyroidectomy may prevent the development of the disease, specially in affected families, and avoid the fatal outcome of delayed medullary thyroid carcinoma diagnosis.
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PMID:[Early diagnosis of multiple endocrine neoplasia type 2 (MEN 2) by detection of mutated RET proto-oncogene carriers]. 970 52

The camptothecin derivative topotecan has been postulated to mediate its antitumor effect through a drug-induced increase in covalent topoisomerase I-DNA complexes. If this hypothesis is correct, then schedules of exposure to topotecan that maximize the number of topoisomerase I-DNA complexes should produce the greatest cytotoxicity. We identified schedules of exposure to topotecan that maximize levels of complexes in vitro and used these schedules to postulate effective schedules of exposure in vivo in a mouse xenograft model. Unexpectedly, K+-SDS precipitation assays quantitating covalent topoisomerase I-DNA complexes showed that Daoy medulloblastoma and Rh30 rhabdomyosarcoma cells became refractory to drug-induced increases in complexes after an 8-h exposure to 2.5 microM topotecan. In contrast, assays using 10-50 nM topotecan showed that the cells did not become refractory, and more importantly, intermittent exposure to drug increased the level of complexes approximately 2-fold above the maximum level observed after a single drug exposure. The data indicate that continuous exposure to topotecan does not maximize topoisomerase I-DNA complexes and suggest that effective intermittent schedules of exposure to topotecan might be identified. Growth inhibition assays confirmed this hypothesis and showed that growth inhibition by topotecan was extremely schedule dependent in Rh30 cells but not in Daoy cells. Xenograft studies showed that schedules modeled after the in vitro experiments produced complete tumor regressions in mice. Topotecan given daily (0.6-2.2 mg/kg) or every other day (1-3.3 mg/kg) for 2 weeks, repeated every 21 days for three cycles, produced complete regressions of Daoy xenografts; however, daily exposure was required to achieve complete regressions of Rh30 xenografts. We conclude that effective intermittent schedules of exposure to topotecan, based on biochemical parameters, can be identified. The clinical utility of each schedule will depend on the relative antitumor effect compared to the toxic effect on the bone marrow, which usually limits administration of topotecan to patients.
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PMID:Effective schedules of exposure of medulloblastoma and rhabdomyosarcoma xenografts to topotecan correlate with in vitro assays. 971 30

We examined RET protooncogene mutations in sporadic medullary thyroid carcinoma (MTC), using polymerase chain reaction (PCR)-based sequencing. DNA was extracted from tumor tissue and peripheral blood leukocytes of seven unrelated individuals with apparently sporadic MTC. Oligonucleotide primers were selected to amplify exons 10, 11, 13, 15, and 16 of the RET protooncogene, to examine the sequences of codons 609, 611, 618, and 620 of exon 10, codon 634 of exon 11, codon 768 of exon 13, codon 883 of exon 15, and codon 918 of exon 16. Direct DNA sequencing from PCR products was then performed. The results showed that one patient had a somatic mutation at codon 918 (ATG-->ACG), causing a Met-->Thr substitution. One patient had a de novo germline mutation at codon 634 (TGC-->CGC), causing a Cys-->Arg substitution. Another patient had a germline mutation at codon 634 (TGC-->TTC), causing a Cys-->Phe substitution. In the remaining four cases, no RET mutations were found. Unexpectedly, two offspring of the patient (a female) with a germline mutation at codon 634 (TGC-->TTC) harbored homozygous alleles for the mutation; because the father did not carry this mutation, the other affected allele was suspected to have resulted from a de novo germline mutation of paternal origin. One of these offspring was subsequently diagnosed as having MTC. Our findings suggest that all patients with apparently sporadic MTC should be screened for the RET protooncogene by molecular analysis to detect occult or de novo multiple endocrine neoplasia 2 (MEN 2) or familial MTC. This would allow early treatment of affected family members.
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PMID:RET protooncogene mutations in patients with apparently sporadic medullary thyroid carcinoma. 974 64

Inhibitors of topoisomerase I and topoisomerase II have demonstrated synergy when administered sequentially in several tumor models while having a diminished antitumor effect when given concurrently. To explore the potential for clinical sequence-dependent synergy, we instituted a Phase I study of topotecan (a topoisomerase I inhibitor) followed by doxorubicin (a topoisomerase II inhibitor) in patients with advanced malignancies. Thirty-three patients with advanced malignancies or malignancies for whom no standard therapy exists were entered into the study. Topotecan was administered in escalating doses by 72-h continuous infusion on days 1, 2, and 3, followed by a bolus of doxorubicin given on day 5. To explore the hematological toxicity associated with this sequence, bone marrow aspirates were obtained both prior to the topotecan infusion and immediately prior to the doxorubicin in 10 patients to determine by fluorescence-activated cell sorting analysis whether CD34+ cell synchronization was occurring using this sequential schedule. Dose-limiting hematological toxicity occurred at the first dose-level in three of six patients. Therefore, we defined the maximum-tolerated dose (MTD) below our starting dose-level. Further dose-escalation and a new MTD were defined with the addition of granulocyte-colony stimulating factor (G-CSF). The MTD was, therefore, topotecan 0.35 mg/m2/day continuous i.v. infusion on days 1, 2, and 3, followed by doxorubicin 45 mg/m2 on day 5 without G-CSF, whereas the MTD with G-CSF was topotecan 0.75 mg/m2/day by 72-h continuous i.v. infusion, followed by doxorubicin 45 mg/m2 i.v. bolus on day 5. Ten patients with paired bone marrow aspirates obtained before topotecan and before doxorubicin administrations were available for evaluation. In 7 of 10 patients, there was an increase (16.6 +/- 2.9% to 25.0 +/- 3.5%; P < 0.02) in the proportion of CD34+ cells in S-phase 24 h after the topotecan infusion and prior to doxorubicin compared to the pretreatment values, whereas 1 patient had a decrease in the proportion of CD34+ cells in S phase and 2 patients had no change. Topotecan and doxorubicin with this sequence and schedule can be given safely; the dose-limiting toxicity is hematological toxicity. Alterations in the fraction of hematopoietic progenitor CD34+ cells in S-phase may account for the increased granulocytopenia and thrombocytopenia observed at relatively low dose levels of the combination with and without G-CSF.
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PMID:A phase I study of topotecan followed sequentially by doxorubicin in patients with advanced malignancies. 981 46


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