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PubMed1997

N-(Hydroxymethyl) melamines.

1. The N-(hydroxymethyl) melamines are analogs of the antitumor agent hexamethylmelamine (HMM) which do not require bioactivation to exert their antitumor effects. 2. Trimelamol (N2,N4,N6-trihydroxymethyl-N2,N4,N6-trimethylmelamine; TM) was developed as a water-soluble antitumor agent for intravenous administration. 3. Phase I and II trials of TM showed promising activity versus platinum-refractory ovarian cancer, but unfortunately further clinical development was halted due to formulation difficulties. 4. Stable analogs of TM were synthesized in an effort to overcome this shortcoming and these were evaluated in a number of in vitro and in vivo studies. 5. While the stable analogs showed good in vitro cytotoxicity in tumor cell lines, only one analog, CB7646 [bis-N-(hydroxymethyl)trimethylmelamine], showed comparable in vivo antitumor activity to that seen for TM. 6. Both TM and CB7646 were curative in human ovarian and breast cancer xenograft models, including the HX110P ovarian cancer xenograft with acquired resistance to carboplatin. 7. As CB7646 possesses favorable formulation characteristics, relating to its superior stability over that for TM, it is currently being developed for phase I clinical trial. 8. The N-(hydroxymethyl) melamines are capable of overcoming many forms of drug resistance, based on data obtained in in vitro and in vivo studies, and thus show promise as agents in the treatment of heavily pretreated, refractive tumors.

Altretamine↗
PubMed1980

Determination of hexamethylmelamine and metabolites in plasma or serum by gas-liquid chromatography with a nitrogen-sensitive detector.

A gas chromatographic method for the quantitative determination of hexamethylmelamine (HMM) and five of its metabolites in plasma (or serum) is described. After adjustment of the pH of the plasma sample to about 9.5, the compounds are extracted with chloroform containing 5% of isopropanol. Amyl alcohol is added to the extract, which is then evaporated until a small volume remains. An aliquot of this solution is injected into a gas chromatograph equipped with a nitrogen--phosphorus flame ionisation detector. Separation of the methylmelamines is achieved with a 10% Carbowax 20M--2% KOH column. By programming the oven temperature unnecessarily long retention times are avoided. Using 1 ml of plasma, concentrations as low as 5 ng/ml of HMM and its metabolites can be quantitated. The method has been applied to the determination of HMM and metabolites in plasma of patients who received oral doses of HMM.

Altretamine↗
PubMed1993

Application of the periodic bond chain (PBC) theory and attachment energy consideration to derive the crystal morphology of hexamethylmelamine.

The habit (external morphology) of a crystal is controlled by both the external (environmental) conditions of crystallization and the internal (structural) factors of the crystal. In order to separate the effects of the crystal structure and of the solvent and other external factors on the experimentally observed growth habit, the theoretical habit can be derived from the crystal structure using the periodic bond chain (PBC) theory and attachment energy considerations. According to the PBC theory the crystal habit is governed by a set of uninterrupted chains of strong bonds formed in the crystal lattice. In addition, the attachment energy (E(att)) is defined as the energy released per mole when a new layer is deposited on a crystal face. Since the habit of a crystal is determined by the relative growth rate (R) of the various faces, by taking R proportional to E(att), the theoretical habit can thus be derived from E(att). Using this approach, we obtained the theoretical crystal habit of an antitumor drug, hexamethylmelamine (HMM). The possible effect of solvents on the habit modification of HMM is discussed. This technique, based purely on the knowledge of the crystal structure, is directly applicable to other pharmaceuticals in deriving their theoretical crystal habit.

Altretamine↗
PubMed1980

Time dependence of the in vitro cytotoxicity of hexamethylmelamine and its metabolites.

The cytotoxicity of hexamethylmelamine (HMM) and its metabolites pentamethylmelamine (PMM), N,2,2,4,6-tetramethylmelamine (TMM) and hydroxymethylpentamethylmelamine (HMPMM) and of the alkylating agent triethylenemelamine (TEM) were studied on a cell line derived from a human ovarian cancer, by measuring [3H]TdR uptake. After 24 h of incubation all the tested compounds inhibited [3H]TdR uptake, but only at a concentration of 100 micrograms/ml. However, after 120 h incubation, concentrations of 0.1--10 micrograms/ml resulted in highly significant cytotoxicity. HMPMM and TEM were the most active and their effect was not reversed 72 h after their removal. In our in vitro system no metabolism of HMM was observed.

Altretamine↗
PubMed1982

Tumour lysis as a factor affecting blood levels of CEA.

A hypothesis is proposed that tumour lysis may be an important factor affecting blood levels of CEA. This has been explored in an experimental study with a model tumour system, consisting of immune-deprived mice bearing human CEA-producing tumours. Using agents such as irradiation, chemotherapeutic drugs, diphtheria toxin and techniques such as cryosurgery, it has been shown that tumour lysis is important when it is both rapid and extensive. The extent to which this may occur in patients remains uncertain, except in rare instances of dramatic response of malignant disease to treatment.

Altretamine↗
PubMed1983

Clinical correlates of in vitro drug sensitivities of ovarian cancer cells.

Of 89 samples of cancer cells from ovarian cancer patients primary cultures representative of the cancer cell population could be established in 17. The clinical response to polychemotherapy was studied in relation to the inhibition of thymidine uptake by the cultured cells. Cultures of each patient's tumour were exposed to concentrations of the drugs the patients had been given for long enough to reproduce the area under the curve (AUC) of the plasma levels resulting from in vivo dosage. Full agreement was observed between the degree of thymidine uptake inhibition induced by at least one of the drugs administered to the cultured cells and the degree of clinical response. This approach may prove useful in pharmacological studies as a means of obtaining ovarian cancer cell populations representative of human tumours, even though the number of tumours that can be successfully evaluated in vitro is still too small to serve as a sound basis for prediction.

Adult↗
PubMed1983

Pentamethylmelamine (PMM): Phase I clinical and pharmacokinetic studies.

PMM is a water-soluble alternative to HMM. PMM has been administered as an intravenous infusion to 17 patients in a Phase I clinical trial. The dose-limiting toxicities were nausea and vomiting which were observed in all patients at 500 mg m-2 and above. The dose was not escalated above 1300 mg m-2 where nausea and vomiting were severe, prolonged (greater than 24 h) and poorly controlled by anti-emetics. Haematological, hepatic and renal toxicities were not observed. Neurological toxicity was not observed at low doses (less than 500 mg/m2) but could not be determined at higher doses due to intensive anti-emetic therapy. Pharmacokinetic studies (100-500 mg m-2) indicated that PMM plasma levels are dose-dependent and that the PMM disposition-phase half-life is prolonged in patients with abnormal liver function. It is concluded that the severe toxicity of PMM will limit the clinical utility of this compound and hence Phase II trials are not recommended.

Adult↗
PubMed1986

Low central nervous system penetration of N2,N4,N6,-trihydroxymethyl-N2,N4,N6,-trimethylmelamine (Trimelamol): a cytotoxic s-triazine with reduced neurotoxicity.

Trimelamol (N2,N4,N6-trihydroxymethyl-N2,N4,N6-trimethylmelamine) is an analogue of pentamethylmelamine (PMM). In early clinical trials PMM failed to show significant anti-tumour activity in man which was attributed to poor metabolic activation. Trimelamol does not require activation and is therefore expected to be more active in man. PMM caused dose-limiting emesis and sedation whereas Trimelamol is much less neurotoxic in rodents. The relative penetration of PMM and Trimelamol into mouse brain has therefore been examined. Mice receiving PMM at 90 mg kg-1 i.p. were found to have high concentrations of the drug in the CNS compared to plasma (mean brain/plasma ratio 1.04) whereas animals receiving Trimelamol had consistently low CNS concentrations (mean brain/plasma ratio 0.08). This difference did not correlate with plasma protein binding which is greater for PMM (68.2%) than for Trimelamol (17.5%). However, it does appear to be related to lipophilicity. In Phase I clinical trial Trimelamol has proved much less emetic than PMM and causes no acute sedation. It is likely that this reduction in toxicity may be explained by the relatively poor ability of Trimelamol to enter the CNS.

Altretamine↗
PubMed1990

Prognostic factors in advanced epithelial ovarian cancer. (Gruppo Interregionale Cooperativo di Oncologia Ginecologica (GICOG)).

The data on 914 patients enrolled in four randomised trials in advanced ovarian cancer, consecutively conducted by the same cooperative group between 1978 and 1986, were analysed with the aims of: (1) determining the impact of selected prognostic variables on survival; (2) finding, from the interaction of favourable prognostic factors and treatment, an approximate estimate of the magnitude of the survival advantage associated with the use of platinum-based combination chemotherapy. The overall 3-year survival in this series of patients is twice that reported historically (22%; 95% CL 18.7-25.4). The proportional hazard regression model was used to perform the analysis on survival. Residual tumour size, age, FIGO stage and cell type were all independent determinants of survival. Differences in survival from the various prognostic groups were impressive with 5-year survival rates ranging from 7 to 62%. However, these differences were not qualitative (i.e. the kinetics of survival were similar for the best and the worst groups) suggesting that current prognostic factors are of little use for selecting 'biologically' different sub-populations. Platinum-based regimens were associated to an overall prolonged median survival, but this benefit was not observable in the subgroup with most favourable prognosis (less than 2 cm residual tumour size). The implications of these observations for clinical research and ovarian cancer patients care are discussed.

Age Factors↗
PubMed1991

Subrenal capsule assay in selection of chemotherapy after operation for recurrent ovarian cancer.

Forty-six patients with recurrent ovarian cancer were reoperated, and cancer samples for the subrenal capsule assay (SRCA) were collected from 23 of them, whereas this test was not done in the remaining 23 control patients. The SRCA was evaluable in 22 cases (96%). Taken together, no significant difference appeared in the 3 years' survival figures between the groups: seven of 22 patients (32%) with the evaluable SRCA and six of 23 control patients (26%) were alive. However, a further analysis of the data revealed that the SRCA guided the selection of chemotherapy only in 15 patients, whereas tumour samples were resistant to all cytostatics tested in six cases and toxic side-effects limited the clinical application of the test results in the remaining one case. Four of the 11 patients (36%) whose further chemotherapy was strictly chosen based on the SRCA and seven of the 24 patients (29%) whose treatment was based on physician's choice survived at least 3 years. Our conclusion is that the SRCA is of limited value in the selection of second-line chemotherapy in recurrent ovarian cancer.

Adult↗
PubMed1988

An interaction between cytostatic and anticonvulsant drugs.

A young woman with epilepsy had tonic-clonic seizures during antineoplastic therapy with adriamycin and cisplatin. During two courses of cytostatic drug administration peak and trough plasma levels of phenytoin, carbamazepine, and valproate sodium were measured. Lower plasma levels of carbamazepine and valproate sodium were observed after 2 days of antineoplastic therapy. Normal plasma levels of these drugs were found 2 to 3 days after the last cisplatin dose. Impaired absorption or accelerated elimination might explain these results. Phenytoin levels were reduced to 37% of the original values, although the drug was given intravenously. Changed Michaelis-Menten parameters suggest that cisplatin increases the metabolic rate of phenytoin. Another explanation for the decreased drug levels might be an increased volume of distribution. Calculation of this volume from peak and trough levels showed an increase of the volume of distribution during and after chemotherapy.

Adenocarcinoma, Papillary↗
PubMed1977

Acute leukemia after alkylating-agent therapy of ovarian cancer.

To estimate the leukemogenic potential of alkylating agents, we surveyed 70 institutions using these drugs for the frequency of second cancers in patients with advanced ovarian cancer. Thirteen cases of acute nonlymphocytic leukemia occurred among 5455 patients, as compared to 0.62 cases expected (relative risk = 21.0). All 13 had received alkylating agents. Nine also received radiotherapy. The relative risk for patients given chemotherapy was 36.1 and rose to 171.4 for those surviving for two years (rate = 13.75 per 1000 patients per year). To evaluate the role of therapy versus underlying disease, a historical control of 13,309 patients with ovarian cancer in the National Cancer Institute's End Results Program was analyzed. No excess of leukemia was noted in this group, even among 6596 women receiving radiation. The excess of acute nonlymphocytic leukemia, therefore, appears attribute to alkylating agents, although the effect may be enhanced by exposure to radiation, as previously suggested for Hodgkin's disease.

Acute Disease↗
PubMed1978

Advanced ovarian adenocarcinoma. A prospective clinical trial of melphalan (L-PAM) versus combination chemotherapy.

Eighty patients with advanced ovarian adenocarcinoma were treated in a prospective, randomized trial comparing a four-drug combination--hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil--with the oral alkylating agent, melphalan. Treatment with the four-drug combination was associated with a significantly increased overall response rate (75 vs. 54 per cent) (P less than 0.05), more complete remissions (33 vs. 16 per cent) and longer median survival (29 vs. 17 months) (P less than 0.02) but more severe toxicity than occurred with melphalan. Patients with minimal residual disease had a significantly higher overall response rate than patients with extensive residual disease (84 vs. 53 per cent) (P less than 0.05). Patients with advanced disease who achieved a complete remission documented by peritoneoscopy or laparotomy (or both) have a median survival that will exceed three years. The four-drug regimen is more effective than melphalan in the management of advanced ovarian adenocarcinoma.

Adenocarcinoma↗