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)

Twenty-five patients with endocrine-refractory prostatic carcinoma were treated with doxorubicin, 20 mg/m2 given weekly. All patients had prior hormonal therapy (68% had two or more prior hormonal maneuvers), and 21 (84%) had prior therapeutic or palliative irradiation. Median Karnofsky performance status at the time of entry was 70. Hemoglobin was less than 12.0 g/dL in 15 patients. Bidimensional tumors were present in 12 patients in 19 disease sites; four of the 12 patients (33%) responded in eight of the 19 sites (42%); and three of eight patients had a 75% decrease in prostatic nodule size. Ten of 20 evaluable patients had an improvement of 20% or greater in Karnofsky performance status and 67% (14 of 21) had marked improvement in pain. A greater than 50% reduction or normalization of acid phosphatase occurred in 19% and of alkaline phosphatase in 53%. The overall response rate by National Prostatic Cancer Project criteria was 84%. Gastrointestinal toxicity and alopecia were minimal and myelosuppression was not life threatening in any patient.
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PMID:Weekly doxorubicin in endocrine-refractory carcinoma of the prostate. 666 11

Thirty-one patients with measureable metastatic colorectal cancer refractory to 5-fluorouracil-containing regimens received dihydroxyanthracenedione (DHAD, NSC 301739) on a 5-day I.V. schedule administered every 4 weeks. Good-risk patients received DHAD at the starting daily dose of 4 mg/m2 while patients who had had therapy with radiation or myelosuppressive drugs such as mitomycin C or a nitrosourea compound received an initial daily dose of 3 mg/m2. There were no complete or partial remissions in this study. Eight of 30 evaluable patients had disease stabilization. The dose-limiting toxic effect was myelosuppression; neutropenia was more severe than thrombocytopenia. The myelosuppression was more severe in patients who had poor bone marrow reserves and abnormal pretreatment liver functions (serum alkaline phosphatase and serum glutamic oxaloacetic transaminase) levels greater than or equal to 1.5 times normal). DHAD administered by the 5-day dose schedule as used in this study is not effective against colorectal cancer.
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PMID:Phase II evaluation of dihydroxyanthracenedione (DHAD, NSC 301739) in patients with metastatic colorectal cancer. 683 6

A phase I study of human lymphoblastoid interferon (IFN-alpha) was undertaken in patients with acute leukaemia and other malignancies. The pharmacokinetics of intravenous IFN-alpha were also investigated. IFN-alpha was administered to two patients by intravenous (IV) bolus injection at a dose of 5 X 10(6) U/m2; and to a further 37 patients (40 cycles) by continuous intravenous infusion (IVI) for 5, 7, or 10 days at doses ranging from 5 to 200 X 10(6) U/m2/day. Pyrexia, general malaise, anorexia, and rigors were observed at all dose levels; three patients became hypotensive. Myelosuppression occurred in all patients, including seven without bone marrow infiltration. Transient rises in alkaline phosphatase and transaminases (SGOT) were observed in patients receiving daily doses greater than 30 X 10(6) U/m2. Dose-limiting central nervous system toxicity, hyperkalaemia, and hypocalcaemia were encountered at 200 X 10(6) U/m2. In six patients with acute leukaemia there was a fall in the number of circulating leukaemic blasts and in one patient with acute myelogenous leukaemia (AML) the degree of bone marrow infiltration decreased from 99% to less than 5% with cellularity returning to normal. Serum levels of IFN above 1,000 U/ml were achieved with daily doses above 30 X 10(6) U/m2 given by IVI. The maximum safely tolerated daily dose, 100 X 10(6) U/m2 administered for 7 days, is appreciably higher than that used in most previous studies, although even at this level considerable toxicity may be encountered.
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PMID:A phase I study of human lymphoblastoid interferon administered by continuous intravenous infusion. 717 12

Trimetrexate is a folinic acid analogue structurally related to methotrexate, whose primary mechanism of action is believed to be inhibition of dihydrofolate reductase. This reduces the production of DNA and RNA precursors and leads to cell death. Trimetrexate is lipophilic and can passively diffuse across cell membranes including those of Pneumocystis carinii and its mammalian host. To minimise toxicity, trimetrexate must be coadministered with calcium folinate (leucovorin calcium), a reduced folate coenzyme, which is transported into, and protects, mammalian host cells but not P. carinii cells. In noncomparative trials trimetrexate was effective in the treatment of P. carinii pneumonia (PCP) in patients with AIDS who were intolerant of or refractory to cotrimoxazole (trimethoprim/sulfamethoxazole) and pentamidine treatment. In these patients, 2- to 4-week survival rates of 48 to 69% were reported. In a comparative trial in the initial therapy of PCP, trimetrexate was less effective than cotrimoxazole in moderate to severe disease as evidenced by a significantly higher failure rate. Trimetrexate was better tolerated than cotrimoxazole when used in this setting, however. Significantly fewer patients receiving trimetrexate plus calcium folinate discontinued treatment because of adverse events than did patients receiving cotrimoxazole. The most common adverse effect associated with trimetrexate is myelosuppression (neutropenia and thrombocytopenia); this is mitigated by coadministration of calcium folinate and is generally reversible upon dosage reduction or discontinuation. Other adverse effects include increases in serum aminotransferase levels, anaemia, fever, rash/pruritus, and increased alkaline phosphatase or serum creatinine levels. Further research into the use of trimetrexate, including its efficacy as prophylaxis, in combination with other agents and as an oral formulation, is needed to clearly define its role in the treatment of PCP and to identify patients most likely to benefit. Currently, trimetrexate should be considered as an alternative treatment option in immunocompromised patients with moderate to severe PCP who have not responded to or are intolerant of first-line therapy.
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PMID:Trimetrexate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of Pneumocystis carinii pneumonia. 778 90

The ability to target malignant cells for cytotoxicity while sparing normal host tissues has proven to be limited. These limitations have resulted in unacceptable toxicity or insufficiently effective therapy. Continuing investigation of new, potentially useful cytotoxic agents must continue. An alternative approach, also worthy of study, is the selective protection of normal tissues. This approach, used in conjunction with available therapeutic agents, may open the therapeutic window and incrementally enhance the effectiveness of cytotoxic therapy. A variety of methods have been used to protect normal tissues selectively. Regional protection can be used for certain organ systems, such as the oral mucosa. Selective protection on a systemic level is more difficult but agents that seem to protect normal but not malignant tissues selectively are being developed. Among these is amifostine, which was originally selected by the U.S. defense department for study as a radioprotectant. Pre-clinical studies have suggested that amifostine is differentially concentrated in normal tissues but not in malignant tissues. Tissue-specific differences in the activity of alkaline phosphatase, which dephosphorylates amifostine to its active metabolite WR-1065, and in pH are thought to be involved in this relative specificity. Clinical studies indicate that amifostine can reduce the myelosuppression produced by cyclosphosphamide, the combination of cyclophosphamide and cisplatin, and, perhaps, carboplatin. The protective effects of amifostine on nonhematopoietic toxicities are being investigated. Future trials will investigate the integration of amifostine with cytokine-based supportive care in order to define the role of this potentially clinically useful cytoprotectant agent.
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PMID:Amifostine: potential for clinically useful cytoprotection. 785 31

Selective protection of the normal host tissues from the toxic effects of anticancer agents would allow the use of higher, probably more effective, doses of the drugs. It has been demonstrated that delayed high-dose uridine administration after 5-fluorouracil decreases the extent of myelosuppression and causes faster regeneration of the bone marrow. We studied the biochemical consequences of the gastrointestinal toxicity caused by 5-fluorouracil and the potential of high-dose uridine treatment to influence these adverse effects. 5-Fluorouracil caused dose-related decreases in the biochemical parameters (thymidine kinase, sucrase, maltase, alkaline phosphatase) selected as early markers of the impaired metabolic activity of the intestinal mucosa. The nadir of the biochemical changes was reached between 24 h and 72 h after 5-fluorouracil treatment, and complete regeneration of the mucosa took 6-7 days. Delayed high-dose uridine administration failed to mitigate the severity of the gastrointestinal damage that ensued after 5-fluorouracil treatment, but caused significantly earlier regeneration of the mucosa.
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PMID:Biochemical consequences of 5-fluorouracil gastrointestinal toxicity in rats; effect of high-dose uridine. 850 Feb 30

Antineoplastons, which were firstly described by Burzynski, are naturally occurring peptides and amino acid derivatives which control neoplastic growth. We conducted a toxicological study of the Antineoplastons A-10 and AS2-1 in combination with other anticancer agents or radiation in 42 patients, 46 tumors with terminal stage cancer. Antineoplaston A-10 oral formulation and A-10 injectable formulation was administered in 14 and 25 patients respectively. The maximum daily dose was 10 g and 40 g, respectively and the longest term of administration was 610 days and 67 days, respectively. Antineoplaston AS2-1 oral formulation and AS2-1 injectable formulation was administered in 33 and 10 patients, respectively, the maximum daily dose was 12 g and 30 g, respectively, and the longest term was 1070 days and 25 days, respectively. The major adverse effects that may have been related to these agents as used in combination with other conventional chemotherapeutic agents or radiation were general weakness, myelosuppression, and liver dysfunction, but these effects were not seen when either Antineoplaston was administered alone. The minor adverse effects observed in single use of either Antineoplaston A-10 or AS2-1 were excess gas, maculopapullar rash, fingers rigidity, reduced cholesterol, reduced albumin, increased amylase, eosinophilia, increased alkaline phosphatase, headache, hypertension, palpitation, peripheral edema but these adverse effects did not limit to continuation of either agent. The evaluation of the usefulness of the Antineoplastons in combination therapy based on the imaging findings during the course of treatment revealed disappearance or measurable shrinkage of the tumor lasting more than one months as visualized by magnetic resonance imaging or computed tomography was seen in 15 tumors (32.6%). No increase in size of tumor for more than 3 months was observed in 8 (17.4%). The mean survival time of these patients was significantly longer than that in patients with tumors showing progressive increasing (17.52 + 3.31 months vs 4.80 + 0.65 months, p < 0.005). Antineoplaston A-10 and AS2-1 are less toxic than conventional chemotherapeutics and they were useful in maintenance therapy for cancer patients.
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PMID:Toxicological study on antineoplastons A-10 and AS2-1 in cancer patients. 866 95

The pharmacodynamics of etoposide phosphate (Etopophos; Bristol-Myers Squibb Company, Princeton, NJ), a water-soluble prodrug of etoposide, was evaluated in 39 patients with solid tumors after a 30-minute intravenous infusion of escalating doses (equivalent to 50 to 175 mg/m2 of etoposide) on a day 1, 3, and 5 schedule of treatment. Serial blood samples were collected at predose and throughout the 32 hours following day 1 of treatment to determine the area under the plasma concentration-time curve (AUC) of etoposide phosphate and etoposide. Hematology profiles and serum chemistries were determined at predose and twice weekly for approximately 3 weeks after each treatment cycle. Both linear and nonlinear pharmacodynamic models were used to evaluate the relationship between hematologic toxicity and etoposide AUC and patient factors (age, gender, performance status, prior radiation therapy, prior chemotherapy, baseline albumin, bilirubin, alkaline phosphatase, creatinine, leukocyte count, granulocyte count). Etoposide phosphate was converted rapidly to etoposide in vivo. The ratio of the etoposide phosphate AUC to that of etoposide was < or = 1.2% indicating that etoposide was the main species in the systemic circulation. Myelosuppression was the dose-limiting toxicity, and significant decreases in white blood cell and granulocyte counts were noted. Hematologic toxicity was best described by a stepwise linear regression model consisting of etoposide AUC, serum albumin, and bilirubin. In summary, hematologic toxicity produced by the intravenous administration of etoposide phosphate correlates significantly with etoposide AUC and patient factors (baseline serum albumin and bilirubin) in cancer patients.
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PMID:A pharmacodynamic evaluation of hematologic toxicity observed with etoposide phosphate in the treatment of cancer patients. 899 71

The mechanism of action, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of amifostine are reviewed. Amifostine is a prodrug converted by alkaline phosphatase to the active sulfhydryl compound WR-1065. WR-1065 protects normal cells by scavenging free radicals, donating hydrogen ions to free radicals, depleting oxygen, and binding to active derivatives of antineoplastic agents. The immediate conversion of amifostine to WR-1065, its small volume of distribution, and the limited amount of drug and metabolite recovered in the urine suggest that amifostine is rapidly dephosphorylated and enters cells as its active metabolite. The selectivity of amifostine for normal tissue is hypothesized to be a results of the decreased vascularity of tumors, decreased activity of alkaline phosphatase in tumor cells, and pH dependence of WR-1065 uptake. In clinical studies, amifostine decreased the frequency of cisplatin-induced nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression. Amifostine has demonstrated an ability to decrease the hematologic toxicity of cyclophosphamide, carboplatin, mitomycin, and antineoplastic drug combinations. Amifostine has FDA-approved labeling for use in reducing cumulative renal toxicity in patients receiving repeat doses of cisplatin for advanced ovarian cancer and non-small-cell lung cancer. The recommended dose in adults is 910 mg/m2 administered as a 15-minute infusion 30 minutes before the start of chemotherapy. The major adverse effects of amifostine include hypotension and emesis. The benefits of amifostine must be weighted against its potential adverse effects, and the drug's impact on the efficacy of antineoplastics should be further investigated. Amifostine has shown promise in protecting non-malignant cells from the toxic effects of antineoplastics, apparently without compromising toxicity against cancer cells.
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PMID:Amifostine for protection from antineoplastic drug toxicity. 977 47

2-Chlorodeoxyadenosine (2-CdA) is a purine nucleoside analogue with therapeutic activity in low-grade lymphoproliferative disorders. In addition, 2-CdA has a potent myelosuppressive effect, and it has been shown to be toxic to malignant myeloid cells both in vitro and in vivo. In this pilot study we treated nine patients who had advanced myelofibrosis with myeloid metaplasia (MMM) and progressive hepatomegaly or symptomatic thrombocytosis after therapeutic splenectomy. 2-CdA was administered at 0.05-0.1 mg/kg/d for 7 d for one to five treatment cycles. A reduction in liver size associated with marked improvement in fatigue and control of thrombocytosis and leucocytosis was achieved in seven of the nine patients (78% response rate). In four of the seven responding patients the reduction in liver size was durable (4-28 months) and was associated with a decrease in serum alkaline phosphatase levels. However, no patient had improvement in anaemia, and two of the seven initially responding patients have since died of acute leukaemia or progressive disease. Improvement in bone marrow fibrosis was noted in two of five available post-treatment marrow examinations. Toxicity was mainly myelosuppression, which was severe in two patients. 2-CdA may be considered a palliative therapeutic agent after splenectomy in noncytopenic patients with MMM who have progressive hepatomegaly or extreme thrombocytosis.
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PMID:2-Chlorodeoxyadenosine treatment after splenectomy in patients who have myelofibrosis with myeloid metaplasia. 969 87


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