Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0854467 (myelosuppression)
 5,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fifty-seven patients with unresectable metastatic colorectal cancer, after failing all conventional chemotherapy, were treated with mitomycin C (MMC) regional intra-arterial infusion. The regional artery (eg, hypogastric, hepatic, etc) was approached percutaneously via the femoral artery and MMC at a dose of 20 mg/m2 in 100 ml of 5% dextrose in water was infused for a 1-hour period; treatment was repeated every 6-8 weeks. Of 51 evaluable patients, five had objective response (three with pelvic tumor, one with liver and lung tumors, and one with liver tumors), 28 had stabilization of tumor, and 18 had no response. Median survival times for the responders, stabilized patients, and nonresponders were 46+, 39, and 22 weeks, respectively, with an overall survival of 32 weeks. The major side effect was necrotizing cellulitis occurring in the buttock following the pelvic infusion. Myelosuppression was manageable and other toxic effects were mild. Using the high-performance liquid chromatography method (total of 25 measurements), the average MMC levels in the peripheral circulation were 205, 62.4, and 16.0 ng/ml, respectively, immediately after injection and 1 and 2 hours following intra-arterial infusion. By 4 hours, no MMC could be detected in the peripheral circulation.
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PMID:Regional intra-arterial mitomycin C infusion in previously treated patients with metastatic colorectal cancer and concomitant measurement of serum drug level. 643 75

Thirty-five patients with advanced cancers were treated with estramustine phosphate tablets (Estracyt). Doses ranged between 420 mg and 700 mg daily. One partial response was documented in a hormone resistant prostatic cancer patient. Four minor responses (less than 50% responses, or less than one month more than 50% response) were obtained; one in a hormone resistant prostatic cancer, two in metastatic colorectal cancers; and another in a malignant melanoma. Toxicity phenomena included nausea (9/35 - 25%), water retention (4/35 - 11.5%) and mild elevation of alkaline phosphatase (2/35 - 6%). Other toxicity effects were vaginal bleeding in two women, acne in one woman and mild pruritus in another patient. Myelosuppression and immune suppression were not significantly detected.
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PMID:Oral estramustine phosphate (Estracyt): a broad phase II study. 659 4

Amsacrine was administered to 73 evaluable patients with previously treated malignant lymphoma in the Southwest Oncology Group. The drug was administered iv every 3 weeks at a dose of either 90 mg/m2 to poor-risk patients (38 patients) or 120 mg/m2 to good-risk patients (35 patients) in 500 ml of 5% dextrose in water over 1 hour. The overall complete plus partial response rate is 16% (12 responses among 73 evaluable patients), with a response duration of 1-33 months. The dose-limiting toxic effect was myelosuppression, with leukopenia in 29 patients and thrombocytopenia in 18 patients. Our experience in the Southwest Oncology Group demonstrates the activity of amsacrine in malignant lymphoma.
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PMID:Phase II study of amsacrine (m-AMSA) in advanced lymphomas: a Southwest Oncology Group study. 668 39

Pentamethylmelamine (PMM) is a water-soluble monodemethylated derivative of hexamethylmelamine and has a similar spectrum of activity against murine tumors. Unlike hexamethylmelamine, it is suitable for parenteral administration. We conducted a phase I trial of PMM given as a weekly 1-hour iv infusion to 34 extensively pretreated patients with advanced solid tumors. Eight dose levels ranging from 80 to 1500 mg/m2 were studied. A median of three infusions (mean, 4.2; range, 1-24) were given to each patient. Severe nausea and vomiting was dose-limiting at 1500 mg/m2; it was unresponsive to antiemetics and persisted up to 48 hours. Mild to moderately depressed levels of consciousness were seen in one third of the patients at dose levels of greater than or equal to 750 mg/m2. Consistent dose-related myelosuppression was not observed. Hepatocellular toxicity manifested by elevated serum transaminases occurred sporadically, usually in patients with liver metastases, but could not be unequivocally attributed to the drug. No complete or partial tumor responses were noted. At each dose level, the pharmacokinetics of PMM disappearance from plasma were studied in one to three patients with a gas chromatograph-mass spectrometer assay which exclusively measured the unmetabolized drug. The data obtained wee consistent with a two-compartment model of drug distribution, with a mean dose-independent terminal half-life of 143 minutes (range, 43-370). Peak drug levels were directly proportional to dose. The relative lack of myelotoxicity would make PMM an attractive candidate for addition to combination regimens if antitumor activity at tolerable doses could be documented. On this schedule, the recommended dose is 100 mg/m2 for phase II trials.
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PMID:Phase I trial of pentamethylmelamine: a clinical and pharmacologic study. 679 19

Indicine-N-Oxide is the water soluble N-oxide of the pyrolizidine alkaloid indicine recently evaluated in Phase I trials. Initially in a weekly times four schedule, twenty-nine patients were treated with a dose range of 1.0 to 7.5 g/m2 per week. Fifteen of 40 of the courses of four doses were interrupted by myelosuppression which prohibited completion of the course. Therefore, an intermittent schedule was evaluated utilizing single doses repeated every 3-4 weeks. Twenty-six patients were treated at doses of 5 to 10 g/m2. Myelosuppression is the dose limiting toxicity of both schedules with thrombocytopenia being more severe than leukopenia. Myelosuppression is predictable and reversible on the intermittent schedule. It is more severe in patients with heavy prior treatment. Partial responses were seen in four patients, one with a mucoepidermoid carcinoma of the salivary gland and three with adenocarcinoma of the colon. Phase II studies are planned at a starting dose of 7.5 g/m2 every 3-4 weeks in patients with no prior treatment and 5 g/m2 in patients with prior treatment.
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PMID:Phase I trial of Indicine-N-Oxide on two dose schedules. 683 92

Previous studies in vitro on the influence of extracellular protein binding of Teniposide (VM26) and Etoposide (VP16-213) on subsequent cellular uptake by experimental murine tumor cells [Cancer Res 38:2549 (1978); Drug Metab Rev 8:119 (1978)] suggested that a timed-sequential combination of VM26 and VP16-213 may increase the bioavailability of VP16-213. This was studied clinically in six cancer patients with ascites (five ovarian, one rectal) whereby VM26 (20 mg/m2) was given i.p. 2 h prior to VP16-213 (100 mg/m2; i.p.) In some patients, this regimen was administered i.v. The i.v. regimen was found to be more toxic (myelosuppression, nausea, vomiting) than i.p. regimen at same doses of drugs. Several patients remained stable to disease during 1-2 courses of therapy (3 weeks per course), one patient had partial remission, and has been stable in her disease for more than 4 months. In two patients, plasma and ascites fluid was analyzed for VP16-213 and VM26 by a new reverse-phase high performance liquid chromatography method. Both VM26 and VP16-213 could be eluted isocratically (28% v/v acetonitrile in water) from a c18 column with retention times of 6.6 and 13.3 min, respectively. Subsequent pharmacokinetic analysis of one patient suggests that protein binding displacement of VP16-213 in plasma and perhaps ascites fluid increased the pharmacokinetic volume of distribution (28 l) and reduced the elimination half-life (12 h). The data suggests that VP16-213 is distributed more widely in the body and is represented by a single compartment pharmacokinetic model. Analysis of VM26 in ascites and plasma suggests that the so-called "deep pharmacokinetic compartment" represents ascites equivalent space and that the plasma concentration represents VM26 as free and protein-bound drug in kinetic distinguishable compartments. Determinants of drug action are potentially composed of a multiplicity of physiological, biochemical, and other factors. The potential for manipulating the pharmacodynamic properties of drugs to achieve greater therapeutic potential needs further study.
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PMID:Combination chemotherapy of the epipodophyllotoxin derivatives, teniposide and etoposide. A pharmacodynamic rationale? 708 56

Edatrexate (10-ethyl-10-deaza-aminopterin, or 10-EDAM) is a water-soluble antifolate which is under study in a variety of malignancies. Edatrexate demonstrated greater antitumor activity than methotrexate in several solid tumor models and xenografts, which may be due to a more extensive formation of polyglutaminates within tumor cells by edatrexate metabolites. Phase I studies have recommended a dose of 80 mg/m2 i.v. weekly for tumor specific trials. When used with leucovorin, edatrexate doses more than 10 times as high have been found to be well-tolerated. Dose-limiting toxicity is mucositis, with leukopenia and thrombocytopenia being less prominent. In three Phase II trials without leucovorin in non-small cell lung cancer, edatrexate has shown an overall objective major response rate of 17% in 66 previously untreated patients (95% C.I.: 9-28%), making it one of the more active single agents in this malignancy. With its relatively low degree of myelosuppression, edatrexate has been an attractive agent for use in combination. To date, trials combining this drug with mitomycin plus vinblastine, cisplatin plus cyclophosphamide, paclitaxel, and carboplatin have been initiated. The encouraging response rates and low degree of toxicity make this agent interesting for further investigation in non-small cell lung cancer.
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PMID:Edatrexate studies in non-small cell lung cancer. 755 28

Etoposide phosphate, a water soluble prodrug of etoposide, has several potential advantages including easier and more rapid administration, avoidance of large fluid loads, and elimination of hypersensitivity reactions and other problems related to the solubilizer. This randomized Phase II study was done to evaluate the efficacy and toxicity of etoposide phosphate and etoposide, when used in combination with cisplatin in the treatment of patients with small cell lung cancer. Previously untreated small cell lung cancer patients were randomized to receive cisplatin in combination with molar equivalent does of either etoposide or etoposide phosphate. The patients were evaluated with respect to response rate, time to progression, survival, and toxicity. Response rates with etoposide phosphate and etoposide were 61% (95% confidence interval 55-67%) and 58% (95% confidence interval 52-64%), respectively (P = 0.85). Median time to progression was 6.9 months for patients who received etoposide phosphate and 7.0 months for those with etoposide (P = 0.50). For extensive stage disease patients, median survival with etoposide phosphate was 9.5 months versus 10 months for etoposide (P = 0.93). The corresponding median survivals for patients with limited stage disease were > 16 months and 17 months, respectively (P = 0.62). Myelosuppression was the most common toxicity; Grade 3 and 4 leukopenia occurred in 63% of patients receiving etoposide phosphate compared with 77% receiving etoposide (P = 0.16). The combination of etoposide phosphate and cisplatin is effective in the treatment of small cell lung cancer, and can be administered with acceptable toxicity. This study was not designed to be a formal Phase III comparative trial, but the efficacy and toxicity observed with this regimen were found to be similar to a standard etoposide/cisplatin regimen, using molar equivalent etoposide doses. Etoposide phosphate is preferable to etoposide because it is easier to use.
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PMID:Etoposide phosphate or etoposide with cisplatin in the treatment of small cell lung cancer: randomized phase II trial. 755 61

The effect of an oral treatment with the Kampo formulation Juzen-taiho-to on the toxicity caused by the intraperitoneal administration of 15 mg/kg carboplatin (CBDCA) 9 times (on days 3, 4, 5, 6, 7, 8, 10, 11 and 12) was examined in ddY mice, which were subcutaneously inoculated with sarcoma 180 (S-180) cells on day 1. White blood cell counts, platelet counts, bone marrow cell counts, relative spleen and thymus weight, food intake and body weight decreased significantly, to about 29%, 13%, 14%, 59%, 36%, 42% and 72% of the control levels, respectively, and serum glutamic-oxaloacetatic transaminase, serum glutamic-pyruvic transaminase and relative stomach weight increased significantly, to about 4, 6 and 3 times the control levels, respectively, by the treatment with CBDCA. However, the blood urea nitrogen and serum creatinine were only slightly increased compared to the control value. Co-treatment with 1.7 g/kg of a lyophilized water extract of Juzen-taiho-to once a day 12 times (on days 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14 and 15) prevented both the decreases and increases caused by CBDCA to near the control levels without reducing the antitumor activity of CBDCA against S-180. The inhibitory effect of Juzen-taiho-to against CBDCA-induced myelosuppression was similar to that against 3.0 mg/kg cisplatin (CDDP) 9 times, while CBDCA-induced myelosuppression was more serious in comparison with CDDP. Therefore, these findings indicate that Juzen-taiho-to could be an effective drug for protecting against the side effects induced by CBDCA in the clinic as well as by CDDP.
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PMID:Protective effect of juzen-taiho-to against carboplatin-induced toxic side effects in mice. 765 24

The polyethoxylated castor oil, Cremophor EL (Cremophor) is approved for human use as a vehicle for oral and intravenous administration of water-insoluble compounds. Cremophor has also previously been shown to reverse the multidrug resistance phenotype at clinically acceptable doses. This study demonstrates that doses of Cremophor in the range of 25-50 microliters/kg intravenously (i.v.) administered 1 day prior to near-lethal irradiation protected the regenerative capacity of the marrow, resulting in haematopoietic radioprotection and long-term survival of near-lethally-irradiated mice. In normal mice, Cremophor administration (1) markedly reduced the level of serum haematopoietic inhibitory activity 4-8 h following injection; (2) resulted in a transient decrease in femoral bone marrow cellularity and upregulated B220 (B cells), and 7/4 (neutrophils and activated macrophages), but not Thy-1 (T-cells) surface antigen expression in bone marrow cells within 24 h of injection; and (3) transiently elevated the incidence of both primitive and committed haematopoietic progenitor cells detected in clonal agar culture within 48 h of injection. Bone marrow progenitor cell content, and peripheral blood white cell, platelet and reticulocyte counts were unaffected. This suggests that the haematopoietic radioprotection and recovery observed in irradiated mice pretreated with Cremophor may be the result of accessory cell activation and/or modulation of accessory factors regulating haematopoietic progenitor cells. Our data suggest a potential clinical use of Cremophor as an adjunct to, or as a substitute for, cytokines to minimize myelosuppression following cytotoxic therapy.
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PMID:Haematopoietic radioprotection by Cremophor EL: a polyethoxylated castor oil. 785 17


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