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Biomedical subjects

N Haim

Publications and source records attributed to N Haim.

At least 91 records · Page 5Linked to original sources
PubMed1988

Treatment of diffuse histiocytic and diffuse mixed non-Hodgkin lymphomas with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP).

During 1977 to 1985 90 patients with large-cell non-Hodgkin lymphoma (diffuse histiocytic or diffuse mixed according to Rapport classification) were treated by the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) with a mean follow-up of 41 months. Thirty-four patients were treated with radiation therapy as well. The mean number of CHOP cycles to achieve complete response was 4.0 and the mean total number of cycles was 6.6. For 78 patients it was possible to calculate relative dose intensity (RDI) for each drug and the average RDI. Sixty-four patients (71%) achieved CR. The actuarial 5-year survival rate of all patients was 52%. The median RDI for cyclophosphamide was 0.72, for doxorubicin 0.70, for vincristine 0.69 and the median average RDI was 0.69. The following favorable prognostic factors were found to be of statistical significance: female sex and stages I-III as compared to stage IV. The 5-year survival rate for stage I & II patients treated by CHOP plus radiotherapy was 70% as compared to 55% for those treated by CHOP only; this difference was not statistically significant.

Adolescent↗
PubMed1987

Peroxidase-catalyzed metabolism of etoposide (VP-16-213) and covalent binding of reactive intermediates to cellular macromolecules.

The horseradish peroxidase- and prostaglandin synthetase-catalyzed oxidative metabolism of the highly active anticancer drug, etoposide (VP-16-213), has been studied in vitro. This oxidation of VP-16 resulted in the formation of VP-16 quinone, an aromatic VP-16 derivative and the corresponding aromatic VP-16 quinone. This oxidative metabolism of VP-16 also resulted in the formation of reactive species that covalently bound to exogenously added DNA and heat-inactivated microsomal proteins. The peroxidase-catalyzed binding was time dependent and required the presence of cofactors (hydrogen peroxide or arachidonic acid). The prostaglandin synthetase/arachidonic acid-catalyzed metabolism and binding of VP-16 were inhibited by indomethacin, an inhibitor of the cyclooxygenase, and were shown to involve the peroxidative arm of prostaglandin synthetase. Our studies show that the protein covalent binding species were formed as a result of O-demethylation of the drug as shown by the loss of specifically labeled (O-14CH3) radioactivity from O-methoxy group and by incubating proteins with VP-16 quinones. In contrast, the covalent binding intermediates for DNA appeared to be different and VP-16-derived quinone methides are suggested as DNA binding species. Co-oxidation of VP-16 and the related drug, VM-26, during prostaglandin biosynthesis may be an important pathway for the metabolism of these agents and may play a role in their cytotoxic properties.

Animals↗
PubMed1987

In vitro metabolism of etoposide (VP-16-213) by liver microsomes and irreversible binding of reactive intermediates to microsomal proteins.

We have studied the metabolism of VP-16-213 (etoposide, VP-16), an antitumor agent, by mouse liver microsomes to reactive intermediates and the subsequent covalent binding to microsomal proteins. This metabolism was shown to involve the O-demethylation of VP-16 and resulted in the formation of a 3',4'-dihydroxy derivative (DHVP-16) which was identified by both HPLC and mass spectrometry. The formation of DHVP-16 was cytochrome P-450-mediated as indicated by its dependence on NADPH, its increased production following treatment of mice with phenobarbital, and its marked inhibition by SKF-525A and piperonyl butoxide. Furthermore, DHVP-16 formation required oxygen. Microsomal incubation of VP-16 resulted in an irreversible binding of the drug to the proteins, which was also shown to be cytochrome P-450 dependent. The covalent binding of the VP-16 metabolite(s) was inhibited by DHVP-16 in a dose-dependent fashion, suggesting that the reactive intermediates that bound to proteins were derived from DHVP-16. Electron spin resonance studies indicated that the same semiquinone radical was formed during enzymatic (oxidation or reduction) metabolism of DHVP-16 and the o-quinone derivative of VP-16 (VP-16-Q). VP-16-Q and its semiquinone radical are suggested to be the bioalkylating species.

Animals↗
PubMed1987

Treatment of advanced gastric cancer with DDP (cisplatin), adriamycin, and 5-fluorouracil (DAF).

Sixteen evaluable patients with advanced gastric cancer who had no prior therapy were treated intravenously with cisplatin (DDP) 20 mg/m2/day on days 1-5 and with Adriamycin 40 mg/m2 and 5-fluorouracil 600 mg/m2 on day 1 (DAF) every 3 weeks. There were five objective partial responses, giving a response rate of 31%. Five patients had minor responses, and 5 others achieved disease stabilization. The median duration of response for responders was 10 months, and the median time to tumor progression in nonresponders was 6 months. The overall median survival was 12 months (responders 14 months, nonresponders 9 months; NS). Most patients had a subjective improvement, including disappearance of abdominal pain (7/9) and gastrointestinal bleeding (5/7). The drug toxicity was moderate to severe. The primary nonhematologic toxicities were nausea and vomiting (in all patients), severe weakness (44%), and parasthesias (31%). Eight patients (50%) experienced significant bone marrow suppression. The DAF combination appears to have some activity in patients with advanced gastric cancer. However, further efforts in new drug development and other combinations are needed to improve the results of chemotherapy in stomach cancer.

Adenocarcinoma↗
PubMed1986

Non-Hodgkin's lymphoma presenting with spinal epidural involvement.

Cord compression was noted at presentation in 10 of 453 (2.2%) previously untreated non-Hodgkin's lymphoma patients seen at the Northern Israel Oncology Center between 1968 and 1983. A prodromal phase of local back pain occurred in eight patients, persisting up to 1 year, followed by a second phase of rapidly progressive signs of cord compression. Five of the ten patients presented with primary spinal epidural involvement (Stage IE), whereas the others had Stage IIE and IIIE (one patient each) and Stage IV, with bone and bone marrow involvement (three patients). All patients had unfavorable histologic diagnoses, mostly of the intermediate grade malignancy types according to the Working Formulation. The patients were treated by radiotherapy (two patients), chemotherapy (three patients), or both modalities (five patients). Seven of the ten patients achieved complete remission, but four of them have subsequently had relapses (two patients in bone, one in central nervous system, and one in mediastinum). The 5-year actuarial survival and 3-year relapse-free survival were 66% and 32%, respectively. Median survival has not been reached after a mean follow-up of 34 months. Non-Hodgkin's lymphoma with spinal epidural involvement at presentation is an aggressive disease. An intensive treatment combining irradiation with chemotherapy, and surgery as needed, is suggested in order to achieve good local response and long-term survival.

Actuarial Analysis↗
PubMed1986

Peroxidative free radical formation and O-demethylation of etoposide(VP-16) and teniposide(VM-26).

The peroxidative activation of the antitumor drugs, etoposide (VP-16) and teniposide (VM-26), has been studied in vitro. Both of these drugs, in the presence of horseradish peroxidase or prostaglandin synthetase, formed phenoxy radical intermediates. Furthermore, this activation also resulted in the formation of two metabolites from each of the drugs. Using HPLC and mass spectrometry, one of the metabolites was shown to be the reactive o-quinone derivative of the parent drug which resulted from the peroxidative O-demethylation. It appears that O-demethylation catalyzed by peroxidases may be an important mechanism for the formation of reactive intermediates and may play a role in the mechanism of action of VP-16 and VM-26.

Chromatography, High Pressure Liquid↗
PubMed1985

Postirradiation soft tissue sarcoma occurring in breast cancer patients: report of seven cases and results of combination chemotherapy.

Seven cases of soft tissue sarcoma developing after primary or postoperative radiotherapy for breast carcinoma are reported. The sarcomas occurred within the irradiated volume, after a latent period of 4-26 years. These cases conform well to established criteria for the diagnosis of radiation-induced sarcoma. Chemotherapy, consisting of the four-drug combination CYVADIC (cyclophosphamide, vincristine, adriamycin, DTIC) was employed in six of the seven patients. Only two of them achieved partial remission, lasting only 2 and 3 months, respectively. The effectiveness of adriamycin-containing chemotherapy regimens in soft tissue sarcomas as well as the remote hazard of radiation-related sarcoma in primary or postoperative breast irradiation are discussed.

Adult↗
PubMed1985

Combined-modality treatment of inoperable lung cancer (i.v. immunotherapy, chemotherapy, and radiotherapy).

Patients with inoperable non-small cell carcinoma of the bronchus were treated by iv methanol extraction residue of bacillus Calmette-Guérin (MER) followed by combination chemotherapy with methotrexate, doxorubicin, cyclophosphamide, and lomustine (MACC). Radiotherapy was added in patients with localized disease. MER was given iv in four weekly courses. The dose ranged between 0.1 and 0.8 mg/m2/course and was determined according to the skin reactivity to MER. None of the 19 patients treated with iv MER had an objective tumor response during immunotherapy. Five of 16 evaluable patients receiving MACC (31%) achieved partial response. The overall median survival for all 17 patients treated was 11 months according to the protocol. During immunotherapy the following side effects were observed: all patients had fever and chills and most had malaise, nausea and/or vomiting, and headache. Transient abnormalities of liver function tests were found in six patients, and in one patient roentgenographic changes suggestive of lung granulomas were seen. The side effects were more severe during the first course than in the further treatments. Side effects of the MACC combination were comparable to those observed in previously reported studies. Immunological monitoring performed during immunotherapy revealed that iv MER had an unfavorable effect on the immune system. Following four courses there was a decrease in the in vivo skin reactivity to MER and to five recall antigens. Twenty-four hours after the initiation of iv MER there was a tendency for decrease in the lymphoproliferation to phytohemagglutinin, an increase in the indices of the adherent cell suppressor system and the prostaglandin-related suppressor system, and an increase in the percentage of adherent mononuclear cells. No consistent changes in serum lysozyme were found. A transient increase in the total number of peripheral blood leukocytes and a decrease in the number of lymphocytes were noticed 24 hours after iv MER. Taking into account the results of the immunological studies and the overall therapeutic results, we do not feel justified in continuing to use this combined modality treatment.

Adenocarcinoma↗
PubMed1984

Further studies on the treatment of advanced gastric cancer by 5-fluorouracil, Adriamycin (doxorubicin), and mitomycin C (modified FAM).

Twenty-two previously untreated patients with advanced gastric adenocarcinoma were treated with a modification of the original 5-fluorouracil, Adriamycin (doxorubicin), and mitomycin C (FAM) combination chemotherapy. The cycles were repeated every 6 weeks. There were four partial remissions and no complete response (overall response rate of 18%, with confidence interval of 0.02-0.34 for a confidence level of 95%). Duration of response ranged between 2.5 and 12 months. The overall median survival was 6.8 months. The median survival of responding patients (13.6 months) and the nonresponders (5.8 months) did not significantly differ. Sex and initial performance status did not influence the response to FAM. Toxicity was mild to moderate, and in only a few patients was it necessary to significantly reduce the drug doses or to prolong the intervals between treatments. Combining the current results with those obtained in a study recently reported the authors in which the original FAM was given to 33 evaluable patients, 11 responders have been seen among 55 consecutive patients with evaluable disease. These results are obviously inferior to those reported by other groups of investigators and led the authors to try another combination chemotherapy.

Adenocarcinoma↗
PubMed1984

The value of serum copper levels in non-Hodgkin's lymphoma.

A study of 306 serum copper levels (SCL) determinations in 115 patients with non-Hodgkin's lymphoma indicates a positive correlation between SCL and the state of disease. Patients with advanced disease (Stages II, III and IV) before treatment, those with active disease while under treatment, or in a relapse had a significantly higher SCL than patients in Stage I or those with no evidence of disease (NED). The mean SCL of patients with Stage I was similar to that of patients with NED. The mean values of these two groups did not differ significantly from that of healthy controls. Histological subtypes, according to the Rappaport classification, has no influence on SCL. Grouping into nodular versus diffuse lymphoma, histiocytic versus lymphocytic lymphoma and favorable versus unfavorable histology failed to demonstrate a difference between the groups. Within each subset a wide range of SCL was evident. However, good correlation was observed with the degree of disease activity. SCL may provide a useful parameter for patient monitoring. In this series, however, SCL was not useful for the prediction of an early relapse.

Adult↗
PubMed1984

Methotrexate-related deaths in patients previously treated with cis-diamminedichloride platinum.

Among 106 patients treated with conventional-dose methotrexate (MTX) following prior therapy with cis-diamminedichloride platinum (CDDP), six died with clinical manifestations of MTX toxicity. Death occurred 6-13 days after the administration of 20-50 mg/m2 MTX. Toxicity included severe stomatitis and myelosuppression, which appeared in all six patients, skin rash in five, and diarrhea in four. Renal failure appeared in five cases and hepatic toxicity in four. All these patients had received MTX earlier without developing any serious toxicity. At the time of the last MTX administration, all had normal blood counts and also normal kidney and liver function tests. Prior therapy with CDDP may be responsible for this relatively high incidence of MTX-related deaths.

Aged↗
PubMed1984

Prostaglandin-related and adherent cell suppressor system in apparently cured Hodgkin's disease patients.

Lymphocyte proliferation (LP) by phytohemagglutinin (PHA) and two suppressor systems of mononuclear cells was investigated in 22 patients with Hodgkin's disease (HD) who were apparently cured at the time of study. The results were compared with those obtained in healthy controls and in a group of patients with inoperable carcinoma of the bronchus. The prostaglandin-related suppressor cell system ( PGSS ) was tested by adding 1 microgram/ml indomethacin to the mononuclear leukocyte cultures. The adherent cell suppressor system ( ACSS ) was tested by removal of the adherent cells on plastic petri dishes. The PGSS index of suppression was defined as the ratio of LP by PHA with indomethacin to LP without indomethacin. The ACSS index was defined as the ratio of the nonadherent cell LP to the total LP. The mean PGSS index in HD patients (1.1 +/- 0.25) was significantly higher (p less than 0.01) than in healthy controls (0.94 +/- 0.2). The ACSS index in HD patients (1.08 +/- 0.47) was also higher (p less than 0.02) than in controls. The LP by PHA value in HD patients (23,908 +/- 14,770 cpm) was significantly lower (p less than 0.001) than in controls (47,151 +/- 17,706 cpm). ACSS values in bronchogenic cancer patients were lower than in HD patients. The LP by PHA value was significantly lower in HD patients compared with bronchogenic carcinoma patients (p less than 0.02). HD patients who had a PGSS index of 1.3 or higher had a significantly lower LP value than those with a PGSS index lower than 1.3.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗