Chemotherapeutic and surgical induction of pathological complete remission and whole abdominal irradiation for consolidation does not enhance the cure of stage III ovarian carcinoma. (17/29)

Thirty-eight patients with stage III ovarian carcinoma were treated with a protocol consisting of an initial phase of induction of remission with cyclophosphamide, hexamethylmelamine, doxorubicin, and cisplatin (CHAD) combination chemotherapy and a second laparotomy for resection of residual tumors, followed by a consolidation phase with curative doses of whole abdominal radiation. Six patients (16%) had stage IIIA disease, ten (26%) IIIB, and 22 (58%) had stage IIIC disease. All patients received three to 14 courses of CHAD chemotherapy with a clinical response rate (complete [CR] and partial [PR]) of 91%. Thirty-three patients underwent the second operation. In 14 patients no residual tumor was found, and in another 11 residual tumors found were totally resected. Thus, 25 of 33 (76%) were classified as in pathological complete remission (PCR) after this operation. Whole abdominal irradiation was well tolerated, although 12 of 29 (42%) of the irradiated patients required more than a 2-week interruption of the treatment course because of leukopenia and/or thrombocytopenia. The actuarial 5-year survival and disease-free survival rates for the whole group were 27% and 17%, respectively, and for the 29 patients who received the complete sequence of the prescribed protocol treatments, 35% and 20%, respectively. A univariate analysis of clinical parameters showed that inherent biological features, such as histology and grade, were the most dominant factors affecting prognosis, and that neither the aggressive surgical approach employed, nor the high-dose whole abdominal irradiation, significantly affected the outcome. The long-term results suggest that although our combined modality protocol was well tolerated, it failed to enhance the cure of stage III ovarian carcinoma. The possible biological and therapeutic vectors affecting this outcome are discussed.  (+info)

First-pass metabolism of pentamethylmelamine in the rat liver. (18/29)

The disposition of pentamethylmelamine (PMM) was studied in the male Wistar rat. PMM (5 mg/kg) was administered intraarterially, i.v. (5 and 10 mg/kg), via the portal vein, and into the duodenum to cannulated and unanesthetized rats (n greater than or equal to 4) via infusion. Parent compound and metabolites were quantified by gas chromatography. The areas under the plasma concentration-time curves of PMM after intraarterial and i.v. administration were equal and twice as large as the areas after portal vein and intraduodenal administration. This indicated insignificant lung metabolism for PMM; the low bioavailability of PMM when given via the portal vein or intraduodenally (in both cases, some 50% of an i.v. dose) was the result of presystemic metabolism in the liver. PMM was completely absorbed after intraduodenal administration, and no intestinal metabolism was observed. Linear kinetic behavior of i.v. PMM was observed in the 5- to 10-mg/kg dose range. The area under the plasma concentration-time curve of the first metabolite N2,N2,N4,N6-tetramethylmelamine was significantly greater when PMM was given via the portal vein or intraduodenally than when given intraarterially or i.v. This indicated either extrahepatic elimination/renal excretion of PMM or the existence of an additional metabolic pathway. However, experiments with adrenalectomized rats and rats with ligated blood flow to the kidneys did not alter the area for the first metabolite. These findings may be explained by the formation of unknown metabolites and/or reactive intermediates of PMM.  (+info)

Pentamethylmelamine (PMM): Phase I clinical and pharmacokinetic studies. (19/29)

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.  (+info)

Low oral bioavailability of hexamethylmelamine in the rat due to simultaneous hepatic and intestinal metabolism. (20/29)

The disposition of both hexamethylmelamine (HMM) after intraarterial, i.v., portal vein, and intraduodenal administration and of pentamethylmelamine following its i.v. administration was studied in male Wistar rats. HMM (5 and 10 mg/kg) and pentamethylmelamine (5 mg/kg) were infused via implanted cannulas into conscious animals (n greater than or equal to 4). Plasma levels of parent compound and of metabolites were determined by gas chromatography. The areas under the plasma concentration-time curves of HMM following its intraarterial and i.v. administration were not significantly different, indicating that HMM was not appreciably metabolized in the lung. Areas under plasma-concentration-time curves of HMM following portal vein and intraduodenal administration were 27 and 8% of the area under the plasma concentration-time curve after i.v. administration, respectively. Absorption of HMM was complete as judged from metabolite data. The reduced bioavailability of HMM intraduodenally was thus a consequence of presystemic elimination in the liver and the gut wall. Extraction ratios (or first-pass effects) of the liver and the gut wall were 73 and 71%, respectively. Linear kinetic behavior of HMM i.v. was observed in the 5- to 10-mg/kg dose range. Extensive gut wall metabolism may have important implications for the antitumor activity mechanism of HMM.  (+info)

Clinical correlates of in vitro drug sensitivities of ovarian cancer cells. (21/29)

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.  (+info)

Four-drug combination chemotherapy (methotrexate, cyclophosphamide, hexamethylmelamine, and CCNU) for non-small cell bronchogenic carcinoma: a Cancer and Leukemia Group B study. (22/29)

Ninety-eight evaluable patients with nonresectable regional or metastatic non-small cell bronchogenic carcinoma were treated with a four-drug combination chemotherapy program of methotrexate, cyclophosphamide, hexamethylmelamine, and CCNU (MCHC). Fifteen partial or complete responses (15%) were obtained, all but one of which occurred in good performance status (0-1) patients. While "responders lived longer than non-responders", this was due more to initial performance status among responding patients than to achievement of partial (greater than 50%) or complete disease regression. Evaluation of those patients with good performance status (PS 0-1), indicated no statistically significant differences in median survival time for complete response and partial response patients compared to patients with "improved" or "stable" disease status in this group. This combination of modestly active single agents produced disappointing results in our lung cancer population. A search for more active single agents in lung cancer is necessary.  (+info)

Cellular and subcellular studies of the biotransformation of hexamethylmelamine in rat isolated hepatocytes and intestinal epithelial cells. (23/29)

The antitumor agent hexamethylmelamine is subject to oxidative metabolic conversion in rat isolated liver and small intestinal cells (conversion 40 times higher in hepatocytes). This N-demethylation is mediated by cytochrome P-450 in the microsomal fractions, and in mitochondrial preparations it has been found to occur via N- methylolpentamethylmelamine . Somehow, pentamethylmelamine, hydroxymethylpentamethylmelamine , or an intermediary metabolite becomes trapped in the intact cell, but the nature of the adduct formed is still unresolved. Pretreatment of rats with 3-methylcholanthrene p.o. caused a 5-fold increase in hexamethylmelamine turnover. Phorone administered in vivo prior to cell preparation (liver and gut) caused an increase in pentamethylmelamine production. The latter results together with results of adding glutathione to cell incubations demonstrate that glutathione contributes to the regulation of cytochrome P-450-mediated N-demethylation of hexamethylmelamine.  (+info)

Time dependence of the in vitro cytotoxicity of hexamethylmelamine and its metabolites. (24/29)

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.  (+info)