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At least 109 records · Page 6Linked to original sources
PubMed1984

Phase-II study of vindesine and hexamethylmelamine in patients with relapsing small cell carcinoma of the lung.

Twenty-five patients with measurable small cell lung cancer relapsing after first-line chemotherapy were treated with vindesine 3 mg/m2 IV on days 1 and 8 and hexamethylmelamine 100 mg/m2 PO on days 1-14, repeated every 3 weeks. Among 18 fully evaluable patients there was 1 partial remission lasting for 111 days. Two patients had disease stabilization for 127 and 152 days, respectively. Fifteen patients had disease progression. The treatment was well tolerated, myelosuppression being the major side-effect.

Adult↗
PubMed1985

Effect of a hepatic activation system on the antiproliferative activity of hexamethylmelamine against human tumor cell lines.

Incubation of hexamethylmelamine for 1 h with human tumor cell lines in culture did not inhibit colony formation at concentrations up to the limit of drug solubility (200 micrograms/ml). When 1-h incubations were carried out in the presence of a 9,000 g rat liver supernatant preparation and an NADPH-generating system, hexamethylmelamine markedly reduced colony formation. Cyclophosphamide inhibition of colony formation was also dependent on the presence of a 9,000 g supernatant preparation and an NADPH-generating system in incubation mixtures. A 1-h incubation of N-methylolpentamethylmelamine (a DNA-alkylating metabolite formed during N-demethylation of hexamethylmelamine) with human tumor cell lines reduced colony formation in the absence of the liver-activating system. Substantial NADPH-dependent N-demethylation of hexamethylmelamine was observed with rat liver, lung, and kidney microsomal preparations. In contrast, little or no HMM metabolism was observed with tumor cells, tumor cell homogenates, or NADPH-fortified tumor cell microsomal preparations. NADPH-dependent formation of cytotoxic metabolites is a prerequisite for antiproliferative activity of hexamethylmelamine against these human tumor cell lines. In vivo activity of hexamethylmelamine against some tumors may require metabolism by normal cells and subsequent transport of active species to the tumor site.

Altretamine↗
PubMed1983

Distribution, metabolism, and irreversible binding of hexamethylmelamine in mice bearing ovarian carcinoma.

The covalent binding of hexamethylmelamine (HMM) and its metabolites was studied in liver, tumor, blood, kidney, spleen, lung, brain, heart, and small intestine after a single IP injection of 2,4,6-14C-hexamethylmelamine (50 mg/kg) to C57Bl/6J female mice bearing 20-day-old M5076/73A ovarian cancer. Covalent binding to tissue macromolecules was measured 2, 10, and 40 h after injection of the drug. At 2 h liver and small intestine showed the highest levels of irreversibly bound metabolites, the lowest being found in brain and heart. Except in the small intestine, where a decrease was observed between 2 and 10 h, the level of covalent binding was constant up to 40 h. HMM metabolism was also studied. Tissue distribution of pentamethylmelamine (PMM), 2,2,4,6-tetramethylmelamine (TMM), and 2,4,6-trimethylmelamine (TriMM) was determined at the three times considered. At 2 h the drug was already extensively metabolized, TriMM being the major metabolite among those determined.

Altretamine↗
PubMed1985

Hexamethylmelamine, adriamycin, and cyclophosphamide (HAC) versus cis-dichlorodiamineplatinum, adriamycin, and cyclophosphamide (PAC) in advanced ovarian cancer: a randomized clinical trial.

After stratification according to diameter of the largest residual tumor, 120 previously untreated ovarian cancer patients were randomized to receive adriamycin and cyclophosphamide in combination with hexamethylmelamine (HAC) or cis-dichlorodiamineplatinum (PAC). The surgical response rates were 66% to HAC and 70% to PAC, with median times to progression of 14 and 22 months and median survival times of 23 and 24 months, respectively. In patients with residual tumor greater than 2 cm the surgical response rates to HAC and PAC were 56% and 63%, with complete response rates of 13% and 21%, respectively. In two of five complete responders to HAC there has still been no progression at 38 and 48 months, with a median response duration of 25 months. Only one of the nine complete responders to PAC has relapsed, at 33 months, while in the eight others response is maintained at follow-up times of 35-64 months. Myelosuppression was generally mild and similar in the two arms. No significant nonhematological toxicity was reported. It is concluded that at a median follow-up time of 36 months HAC is as effective as PAC in terms of response, duration of remission, and survival in previously untreated advanced ovarian cancer.

Adolescent↗
PubMed1981

Prospective study with HEXA-CAF combination in ovarian carcinoma.

The value of combination chemotherapy with HEXA-CAF was analyzed in 31 patients with histologically documented epithelial ovarian cancer in advanced stages (minimal or gross disease). No patient had been previously treated with chemotherapy. Peritoneoscopy with diaphragmatic inspection, peritoneal cytology, lymphography, and chest X-ray were routinely used in staging and restaging the patients. Complete (CR) plus partial (PR) responses were obtained in 13/31 fully restaged patients (41.9%). CR was recorded in seven patients (22.5%) and PR in six patients (19.3%). Remission duration was significantly longer in patients who achieved CR (20 months) than in those who attained PR (9.5 months) (P Less Than 0.01). In all treated patients the median duration of survival was 16.5 months. Survival was significantly longer in patients with CR than in patients who did not achieve CR (P Less Than 0.05). Nevertheless, considering the rate of CR in patients with gross disease (20.6%), HEXA-CAF combination seems a useful but not yet a hopeful treatment for patients with advanced ovarian carcinoma.

Altretamine↗
PubMed1981

Dose-dependent pharmacokinetics of PMM in the rat.

Concentrations of pentamethylmelamine (PMM) and some metabolites were determined in plasma of rats treated with 10 and 50 mg PMM/kg IV. The areas under the plasma levels curve after these doses were 241 and 1,827 mu g/ml X min; plasma clearances were 0.042 and 0.027 l . kg(-1) . min(-1), respectively. These data suggest that PMM pharmacokinetics is dose-dependent in the rat. The N-demethylated metabolite levels were not proportional to the administered dose.

Altretamine↗
PubMed1986

Superior efficacy of trimelamol to hexamethylmelamine in human ovarian cancer xenografts.

A series of eight human ovarian cancer lines grown in nude mice were used to compare the activity of hexamethylmelamine (HMM) and N2,N4,N6-trihydroxy methyl-N2,N4,N6-trimethylmelamine (trimelamol). The tumor lines differed in histological subtype and growth rate. The drugs were administered i.p. at the maximum tolerated dose at alternate days. Differences in volume of treated and control tumors were endpoints of the study. The tumor lines varied widely in sensitivity to HMM and in four lines a T/C% below 25% was achieved. Trimelamol appeared to be more active than HMM and achieved a T/C below 25% in seven tumor lines. Thus far, the drug has demonstrated significant activity in a phase I trial in ovarian cancer patients. Comparative clinical studies of HMM vs trimelamol have not yet been performed.

Altretamine↗
PubMed1978

A comprehensive protocol for management of cancer of the bilharzial bladder.

A randomized clinical trial for the management of bilharzial bladder cancer is presented. A multidisciplinary approach is adopted. The objective of the study is to evaluate the role of adjuvant radiotherapy in improving the results of surgery in deeply infiltrating tumours, and to screen a number of chemotherapeutic agents for their effectiveness in bladder cancer. A large number of cases will be admitted into the study and the results will hopefully help to achieve better results in the management of this disease.

Altretamine↗
PubMed1986

Pharmacokinetics and metabolism of hexamethylmelamine in mice after IP administration.

The pharmacokinetics of hexamethylmelamine (HMM) and its first metabolite (hydroxymethylpentamethylmelamine: HMPMM) following IP bolus dose of 200 mg/kg were studied in mice. The drug concentrations were determined by a sensitive reversed-phase HPLC assay. Thus, for the first time, HMM major hydroxylated and demethylated metabolite plasma levels canbedetermined at the same time. Pharmacokinetic data were analyzed by an original method using a nonlinear cost function minimized by a simplex algorithm. An important property of this computer program is that convergence is ensured in contrast to linear or nonlinear least-square regression analysis, which leads to lack of convergence or to false convergence. Both HMM and HMPMM data fit a one-compartment open model. The parameters obtained indicate that the parent drug would probably be rapidly and completely transformed by the human body into HMPMM.

Algorithms↗
PubMed1989

Randomised trial comparing prednimustine with combination chemotherapy in advanced ovarian carcinoma.

A total of 76 patients with advanced epithelial ovarian carcinoma were randomised to receive 6 months of treatment with either a combination of hexamethylmelamine, 5-fluorouracil, cisplatin and prednimustine or prednimustine alone following initial surgery. Pathologically confirmed response rates were 35% for combination chemotherapy and 28% for prednimustine, and the overall survival was identical for the two groups. Seven patients achieved a pathologically defined complete response, one of whom relapsed at 8 months; the others remain disease-free 18-36 months (median, 23 months) after presentation. The extent of initial surgery significantly affected the survival of patients receiving prednimustine but not of those receiving combination chemotherapy. Prednimustine can produce durable responses in advanced ovarian cancer using a schedule that results in negligible toxicity.

Altretamine↗
PubMed1982

The comparative pharmacokinetics of pentamethylmelamine in man, rat, and mouse.

The pharmacokinetics of pentamethylmelamine (PMM) have been investigated in mouse (Balb C-, CBA/LAC, nude), rat (Wistar), and man. In all three species, PMM was extensively demethylated to N2,N2,N4,N6-tetramethylmelamine and N2,N4,N6-trimethylmelamine, although marked species differences in the rate of metabolism were observed. PMM metabolism was more rapid in the mouse (plasma t1/2 = less than 15 min) than in the rat (plasma t1/2 = 40 min), and slower in man (plasma t1/2 = 102 min) than in either mouse or rat. Furthermore, the peak plasma concentrations of N-methylolmelamines, intermediates generated during oxidative N-demethylation, were correspondingly higher in the mouse (563-773 microM) than in the rat (211 microM), whilst in man they were undetectable (less than 50 microM). In view of the highly cytotoxic nature of N-methylolmelamines, we conclude that these pharmacokinetic differences may be related to the antitumour effectiveness of PMM in mouse, rat, and man.

Altretamine↗
PubMed1984

Pathologic data of prognostic significance for remission induction in advanced ovarian carcinoma.

Sixty-eight patients with "advanced ovarian carcinoma" were entered into an ongoing phase-II trial for remission induction with cis-platinum (DDP) 80 mg/m2 i.v. on day 1 followed by forced saline diuresis, melphalan (L-PAM) 12 mg/m2 i.v. on day 2 and hexamethylmelamine (HMM) 130 mg/m2 p.o. X 14 days from days 8-21 in six monthly cycles following operative resection and/or staging. Fifty-one patients were evaluable for response, ten had not completed six courses and could not be assessed, two patients died early (one probably of toxicity), and five patients refused treatment and follow-up. Thirty-Two patients had serous, endometrioid or undifferentiated carcinomas of the ovary. Of these, 11 (35%) achieved a pathologically proven complete remission (CR), five (16%) were NED after second-look (residual disease in ovary or removed omentum with all other biopsies and cytology washings negative), eight (32%) achieved a partial remission (PR), and three (12%) had progressive disease. None of the seven patients with clear-cell carcinoma and none of the three patients with Mullerian tumor of the ovary responded. Six of nine patients with tumors of uncertain origin or proven metastasis to ovary did not respond to treatment. These preliminary results indicate that advanced ovarian carcinomas form a heterogeneous group of recognizable neoplastic diseases with striking variation in response to treatment.

Adenocarcinoma↗
PubMed1983

cis-Platinum, adriamycin, and hexamethylmelamine versus cyclophosphamide in advanced ovarian carcinoma.

Fifty-three evaluable patients with disseminated ovarian carcinoma (FIGO III or IV) not treated with prior chemotherapy were randomized to receive either combination chemotherapy consisting of cis-platinum 40 mg/m2 IV on day 1, adriamycin 40 mg/m2 IV on day 1, and hexamethylmelamine 150 mg/m2 PO on days 2-10 up to a maximum of 200 mg on a 4-weekly cycle, or moderate-dose cyclophosphamide alone 40 mg/kg given IV intermittently every 3 weeks. Entry was from 1. 11. 1978 until 30. 4. 1981 (last follow-up 31. 10. 1981). Pretreatment characteristics in both groups of patients, regarding median age at diagnosis, median time from diagnosis to chemotherapy, FIGO stage, histology, differentiation grade, type of surgery, residual disease, previous radiotherapy, and median performance status, were comparable. Objective responses were seen in 18 of 27 (66%) of patients receiving cyclophosphamide alone (range 5--32+ months) and in 10 of 26 (38%) of patients treated with the combination (range 3--30+ months), this difference being statistically significant (chi 2 = 4.228; P less than 0.05). The median duration of objective response (11 vs 10 months) and the median survival (12 vs 11 months) were greater in the cyclophosphamide group, but these differences were not statistically significant. The toxicity of the combination was more severe. It is concluded that there is no therapeutic advantage for this combination schedule over the alkylating agent used alone.

Adult↗
PubMed1986

Changes in erythropoiesis due to radiation or chemotherapy as studied by flow cytometric determination of peripheral blood reticulocytes.

Flow cytometric determination of time dependent changes of numbers of reticulocytes in peripheral blood were investigated as a parameter for changes in erythropoiesis induced by radiation- or chemotherapy. Rats irradiated or treated with drugs (such as e.g. cyclophosphamide 100 mg/kg, vincristin 0.2 mg/kg, or mitomycin C 1.0 mg/kg) showed clear changes in erythropoietic activity. Reticulocyte numbers decreased rapidly until day 3-4 after treatment; this period was followed by a gradual increase and normal control values were seen at day 8-11. Radiation effects of doses as low 0.5 Gy could be detected in such a way. Similar studies were performed with patients with ovarian tumors treated with cis-platinum, a drug that may cause non-immune haemolysis. During prolonged treatment some patients showed increasing numbers of reticulocytes, measured at the first day of each hospitalization period, whereas leucocyte and platelet counts stayed more or less constant. Increasing numbers of reticulocytes generally indicates stimulation of erythropoietic activity of the bone marrow (due to increased blood loss); in this study increasing numbers often preceeded a decrease in hemoglobin values later on. Flow cytometric analysis of reticulocytes is therefore a potentially useful tool to detect changes in erythropoiesis, and considered more sensitive for the early recognition of patients that develop anemia, than hemoglobin measurements only.

Altretamine↗
PubMed1992

Phase II trial of intravenous hexamethylmelamine in patients with advanced ovarian cancer.

A Phase II trial of an intravenous preparation of Hexamethylmelamine was performed in ovarian cancer. Patients who had received prior Platinum based chemotherapy and had measurable disease were eligible. Among 15 evaluable patients, there were no objective responses. Two patients did show clinical and laboratory evidence of improvement. Toxicity was predominantly nausea and vomiting with minimal other toxicity. This intravenous form of Hexamethylmelamine has not shown meaningful activity in ovarian cancer patients who have failed prior platinum treatment.

Altretamine↗
PubMed1985

Short term high density systemic therapy for metastatic breast cancer.

Twenty-three patients with metastatic breast carcinoma were induced with a complex systemic therapy regimen in an attempt to ascertain if a complete remission rate greater than 50% could be obtained with intensive drug exposure. The durability of the remissions was observed by discontinuing therapy after 3 cycles in complete remission or after 6 cycles of treatment, whichever was longer. In 13 patients consolidation radiation therapy to the pre-treatment sites of disease was administered after discontinuing systemic therapy. Each 28 day cycle of the drug regimen consisted of pulses of adriamycin, vincristine, dibromodulcitol, prednisone, methotrexate with leukovorin rescue, hexamethylmelamine, bleomycin (discontinued after entry #17), fluoxymesterone, and tamoxifen. Eighteen of the 23 patients achieved complete remissions (78%) and 3 had partial remissions. The median times to treatment failure and survival were, respectively, 12.3 and 19.4 mos. The times for complete remission patients were, respectively, 13.5 and 23.9 mos. Consolidation radiotherapy at greater than or equal to 40 Gy to drug induced pre-study sites of complete remission was associated with first relapses at pre-study sites in 5/30 (17%) instances, compared to 21/35 (60%) in sites not receiving radiotherapy. Side-effects were commensurate with the intensity of the treatment program and are detailed in the text. Although the achievement of a high complete remission rate is promising, the failure to extend their duration beyond that of historical data suggests that additional conceptual and therapeutic approaches need to be explored.

Altretamine↗
PubMed1982

Hexamethylmelamine and hexamethylmelamine hydrochloride.

Methods of analysis of the anticancer drug hexamethylmelamine, its physicochemical properties, its therapeutic uses and its fate in vivo upon oral administration, are described. The data are taken in part from the literature, in part from our own studies. The low solubility of hexamethylmelamine in water has prevented the parenteral administration of the drug to humans. The preparation of the water-soluble monohydrochloride of hexamethylmelamine, which may be suitable for this purpose, is reported, as well as its physicochemical characteristics and methods of analysis.

Altretamine↗
PubMed1990

Cisplatin induced neuropathy: central, peripheral and autonomic nerve involvement.

A prospective study was performed in patients treated with cisplatin to evaluate the occurrence and degree of central, peripheral and autonomic neuropathy and to determine the most accurate method to study this neuropathy. Twelve patients were examined before, during and after treatment. Evaluation included neurologic examination, conventional nerve conduction studies of the median and peroneal nerves and short latency somatosensory evoked potentials (SSER) after median and tibial nerve stimulation. Valsalva maneuvers before and during treatment were performed in 11 patients. Symptoms of peripheral neuropathy paralleled clinical signs. Conventional nerve conduction studies did not seem to be more accurate than clinical examination in determining peripheral neuropathy. SSER appeared to be the most sensitive method for the detection of peripheral nerve impairment. A slowing of central conduction velocity occurred after cumulative doses of 200-400 mg/m2 as measured by SSER. In two patients also some involvement of the autonomic nerves was suggested.

Adenocarcinoma↗