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)

Eleven patients with osteogenic sarcoma (9), Hodgkin disease (1), and mesenchymal sarcoma (1), were treated with 5-fluorouracil (5-FU) and cisplatin (DDP). Myelosuppression and vomiting of variable degrees occurred in all. No responses were seen.
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PMID:5-fluorouracil and cis-platinum in the treatment of refractory solid tumors: a pediatric oncology group phase I-II study. 694 Oct 70

A total of 114 children with solid tumors refractory to conventional therapy were evaluated for response and/or toxic effects after receiving cisplatin at doses of 3.0-4.5 mg/kg with aggressive hydration and mannitol diuresis every 3 weeks; a minimum of two courses was required for evaluation of response (110 patients). Objective responses were noted in 18 patients: rhabdomyosarcoma (three), Wilm's tumor (three), osteogenic sarcoma (three). Ewing's sarcoma (two), neuroblastoma (one), undifferentiated sarcoma (one), hepatoblastoma (one), ovarian teratoma (one), hepatocellular carcinoma (one), embryonal carcinoma of the mediastinum (one), and thymoma (one). Twenty-six patients had some evidence of renal toxicity. Asymptomatic hearing loss was commonly found when audiometry was performed (eight of 18 patients tested). Eight additional patients had symptomatic hearing problems--tinnitus or hearing loss. Myelosuppression was mild. Hypomagnesemia and/or hypocalcemia were common but only one patient had symptoms. Cisplatin, administered at a dose of 3.0 mg/kg with aggressive hydration and mannitol diuresis, is reasonably well-tolerated. Its role in the therapy for those tumors against which it shows activity remains to be determined.
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PMID:Phase II trail cisplatin in refractory childhood cancer: Children's Cancer Study Group Report. 694 56

ICRF-159 is a bis-diketopiperazine derivative active in a variety of preclinical animal tumor models. Because of its poor solubility characteristics, the drug must be given p.o. However, when given by this route at high doses, poor bioavailability was noted. Two interesting preclinical properties of this agent are its antimetastatic effect and the ability to reduce anthracycline cardiotoxicity. Phase I studies have delineated myelosuppression as the major toxicity with GI toxicity also occurring. In phase II studies, interesting activity has been noted in lymphomas and head and neck carcinomas. When ICRF-159 was combined with radiotherapy, prolonged responses were noted in sarcoma and lung carcinoma in small numbers of patients. Further studies are indicated in areas of activity as a single agent and as a potentiator of radiation therapy.
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PMID:Bis-diketopiperazine derivatives in clinical oncology: ICRF-159. 700 Mar 89

Twenty-seven patients with advanced solid tumors (ten with lung cancer, eight with sarcoma, five with melanoma, four with miscellaneous tumors) were treated with high-dose doxorubicin (120 mg/m2) every 3 weeks for a total of 75 courses. As expected, marked myelosuppression was observed, with all patients having a granulocyte count nadir of less than 500 cells/mm3. The median platelet count nadir was 91 X 10(3)/mm3 following the first cycle and 50 X 10(3)/mm3 following the fourth cycle. Moderate or severe stomatitis was seen with 65% of the courses, and 46% of the courses were complicated by fever greater than 101 degrees F. Congestive heart failure was observed in only one patient after five cycles (600 mg/m2) of high-dose therapy. This patient has received 540 mg/m2 of doxorubicin 2 years previously. Radionuclide ventriculography (MUGA) performed serially in 12 patients (eight of whom received 480 mg/m2) and clinical evaluation did not suggest an increased risk of cardiotoxicity at this dose rate. Overall, 11 of 24 (46%) evaluable patients responded (58% if patients with malignant melanoma are excluded). Responses included one complete and three partial responses in eight evaluable patients with lung cancer, one complete and two partial responses in seven evaluable patients with sarcoma, and no objective responses in five patients with malignant melanoma. With appropriate supportive care, repetitive courses of doxorubicin at a dose of 120 mg/m2 can be given to patients of good performance status without a major increase in cardiotoxicity. However, the low complete remission rate, considering the observed toxicity, does not justify routine use of this regimen in patients with solid tumors.
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PMID:High-dose doxorubicin: an exploration of the dose-response curve in human neoplasia. 706 37

Twenty-nine patients with metastatic sarcoma were treated with a combination of methyl CCNU and actinomycin D. Patients with adequate bone marrow reserve received methyl CCNU 100 mg/m2 orally on day 1 and actinomycin D 0.3 mg/m2/day intravenously for five days. Both drugs were repeated every four weeks. Patients with inadequate bone marrow reserve received methyl CCNU 75 mg/m2 and actinomycin D 0.2 mg/m2/day for five days. All patients had received prior chemotherapy and had progressive disease at the start of the study. There was one complete response in a patient with peritoneal mesothelioma which lasted 18 months and the patient is still alive at 38+ months. Ten patients had stable disease including three patients who had responses between 25% to 50%. No responses were seen in 18 patients. The median time to progression for patients with stable disease was five months and for those with progressive disease was two months (P = 0.001). The median survival for patients with stable disease was 20 months compared with three months for patients with progressive disease (P = 0.001). The combination was generally very well tolerated and myelosuppression was insignificant. However, with the dosages and schedule used in this study, the combination of methyl CCNU and actinomycin D does not appear to have significant activity in advanced soft tissue sarcomas. Further studies with this combination are indicated in patients with mesothelioma.
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PMID:A phase II evaluation of methyl CCNU and actinomycin D in the treatment of advanced sarcomas in adults. 726 Aug 72

The addition of misonidazole (MISO) or metronidazole (METRO) to treatment with cyclophosphamide (CY) increased delay to regrowth of 2 experimental tumours. The effect was observed for large an small tumours, was present for doses of MISO that are ineffective for killing hypoxic cells, and required that it be given with, or shortly before CY. Mice receiving combined treatment had more weight loss and myelosuppression than those receiving CY alone, and the Therapeutic Index was lower. MISO caused a marked increase in growth delay when combined with BCNU to treat the KHT sarcoma. This effect was observed for small and large tumours, required simultaneous administration of drugs, and also led to increased host toxicity. There was no therapeutic advantage from combined treatment. Survival of aerobic or anoxic Chinese hamster ovary (CHO) cells was assessed after exposure in vitro to serum from mice that had received CY or BCNU alone. MISO alone, or combined treatment. Results of these experiments suggest that (1) MISO delays the excretion or breakdown of active metabolites of CY, and (2) at a dose that does not kill hypoxic cells, it may selectively "sensitize" hypoxic cells (but not aerobic cells) to the action of BCNU. The presence of other undetermined interactions of BCNU and MISO is inferred from the increased toxicity to (aerobic) normal tissue. Misonidazole or metronidazole should be used with caution in patients who are receiving BCNU or cyclophosphamide.
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PMID:In vivo interaction of anti-cancer drugs with misonidazole or metronidazole: cyclophosphamide and BCNU. 745 21

A total of 33 patients (median age, 44 years) with high-grade, adult soft-tissue sarcoma were treated with etoposide given at 600 mg/m2 in a 72-h continuous infusion and ifosfamide given at 1500 mg/m2 per day for 3 days every 3 weeks. Dose escalation/reduction was protocolled depending on the level of hematological toxicity observed in the preceding course. Overall, 90% of patients had metastatic disease, and the most common histologies were malignant fibrous histiocytoma and leiomyosarcoma. A median of 5 (range, 1-9) courses were given. Of 30 patients who were evaluable for response, 12 (40%) obtained a partial remission, and the median time to progression was 8 (range, 4-13) months. Grade 3-4 leukopenia and thrombocytopenia were seen after 89% and 8% of the courses, respectively; neutropenic fever was seen in half of the patients (15% of courses); and 32% of courses had to be postponed by 7 days or more due to myelosuppression. Dose reduction to below the standard had to be performed in 46% of courses, and dose escalation was achieved in only 13%. The reduced toxicity seen after the addition of granulocyte colony-stimulating factor (G-CSF) in five patients indicates that growth-factor support may enhance the dose intensity of the regimen. The results indicate significant activity for this regimen in adult soft-tissue sarcoma, which may in part be a result of the escalated dose and prolonged mode of administration of the phase-specific agent etoposide. As a result of this pilot series, a phase II study with ifosfamide, etoposide, and G-CSF in advanced adult soft-tissue sarcoma has been initiated by the Scandinavian Sarcoma Group.
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PMID:Treatment of advanced, high-grade soft-tissue sarcoma with ifosfamide and continuous-infusion etoposide. 753 39

The combination of ifosfamide (with mesna uroprotection), carboplatin, and etoposide (ICE) has demonstrated activity in a variety of cancers. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a dipertene compound extracted from the Pacific yew Taxus brevifolia, appeared a good candidate for study as an addition to the ICE regimen (ICE-T) because of its broad antitumor activity, its unique mechanism of action, and its toxicity profile, which was not expected to impact the ICE regimen adversely. In a phase I study, we evaluated the impact of adding escalating doses of paclitaxel (120 mg/m2, 135 mg/m2, 150 mg/m2, and 175 mg/m2) to the ICE regimen in 13 previously untreated (with two exceptions) patients with breast cancer, sarcoma, lung cancer, and adenoid cystic carcinoma. In general, ICE-T was well tolerated with some myelosuppression observed. Responses were seen at all dose levels. To date, the maximal tolerated dose of paclitaxel has not been reached; we are currently administering 175 mg/m2.
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PMID:Phase I study of escalating doses of paclitaxel (Taxol) with fixed doses of ifosfamide, carboplatin, and etoposide. 761 Mar 96

Myelosuppression is the dose-limiting toxicity for nitrosourea chemotherapy. This toxicity predominantly involves modification of the O6 position of guanine with an alkyl moiety. The enzyme responsible for repair of O6-alkylguanine adducts, O6-alkylguanine-DNA alkyltransferase (alkyltransferase), is expressed at low levels in bone marrow (BM) cells. High alkyltransferase expression prevents the cytotoxicity and carcinogenicity of nitrosoureas in several transgenic and in vitro gene transfer models. We used gene transfer using a novel myeloproliferative sarcoma virus (MPSV) based retrovirus (vM5MGMT) to express the human alkyltransferase cDNA (MGMT) in human and murine hematopoietic cells. Transduced K562 cells had very high levels of alkyltransferase expression and significantly increased resistance to 1,3-bis (2-chloroethyl) nitrosourea (BCNU) as compared with untransduced K562 cells. Primary murine BM progenitors showed a high transduction efficiency with vM5MGMT and have increased BCNU resistance in vitro. After BM transplantation with vM5MGMT-transduced BM cells and BCNU treatment of these mice, BM, spleen and thymus had a 10- to 40-fold increase in alkyltransferase expression that persisted for at least 23 weeks posttransplantation. Progenitor cells procured from mice expressing high levels of alkyltransferase also had increased resistance to BCNU. Thus, an MPSV-based retroviral vector transduces mouse and human hematopoietic cells at high efficiency and results in high levels of gene expression both in vitro and in vivo. Overexpression of the alkyltransferase protein may protect hematopoietic progenitors from nitrosourea-induced myelosuppression.
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PMID:Retroviral transduction and expression of the human alkyltransferase cDNA provides nitrosourea resistance to hematopoietic cells. 775 67

Ifosfamide is an active chemotherapeutic agent in the treatment of soft tissue sarcoma. This Phase II study attempted to evaluate the efficacy of the addition of etoposide to ifosfamide administered to patients with recurrent or metastatic soft tissue sarcoma. Treatment consisted of etoposide 100 mg/m2, followed by ifosfamide 2.0 g/m2, daily, for 4 consecutive days. Mesna was administered for uroprotection. Cycles were repeated at 21-day intervals or upon recovery from toxicity. Two partial responses were observed in 19 evaluable patients (response rate 10.5%, 95% confidence interval, 7% to 14%). Response durations were brief at 2 and 6 months. In a subset of 10 patients with gastrointestinal leiomyosarcoma, no responses were observed. Toxicity was generally mild, consisting primarily of myelosuppression and controllable nausea and emesis. No episodes of hematuria were observed. Overall survival for all eligible patients was 10 months (range: 0.2 to 34.7+ months). Etoposide, in this dose and schedule, failed to enhance the activity of ifosfamide in adult soft tissue sarcoma. Additionally, this experience and a review of the literature, suggest that ifosfamide has little activity against gastrointestinal leiomyosarcomas. Continued efforts are needed to identify novel agents with efficacy against these resistant tumors.
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PMID:Ifosfamide and etoposide in the treatment of advanced soft tissue sarcomas. 797 64


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