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At least 343 records · Page 19Linked to original sources
PubMed1987

Pharmacokinetics of hexamethylmelamine in intralipid following hepatic regional administration in rabbits.

Hexamethylmelamine (HMM) is a cytotoxic agent demonstrated to have broad antitumor activity. Poor solubility in aqueous media has precluded significant evaluation of parenteral administration of this drug. A formulation of HMM dissolved in Intralipid has demonstrated excellent tolerance following parenteral administration. The goal of this study was to evaluate the pharmacology of HMM in Intralipid following hepatic regional administration. The routes of administration were intraarterial via the hepatic artery with and without arterial occlusion, i.v. via the portal and jugular veins, and i.p. All animals received a total dose of 10 mg HMM/kg of body weight. Hepatic extraction of HMM was most evident via the portal vein (PV) route [AUC(PV)/AUC(i.v.) = 0.5; P less than 0.05]. Lower plasma levels and areas under the curve (AUCs) were observed for the hepatic artery and hepatic artery-stop flow groups when compared to i.v., but the difference was not significant. Administration i.p. yielded low plasma levels but a very long half-life (88 min). Hepatic tissue levels were highest in the group receiving HMM by the hepatic artery-stop flow route. We conclude that the HMM-Intralipid mixture is well tolerated, that HMM is extracted to a significant degree by the liver following PV administration, and that an i.p. installation of HMM-Intralipid results in prolonged plasma drug levels. This preclinical study supports further efforts at evaluation of parenteral administration of the HMM-intralipid mixture.

Altretamine↗
PubMed1987

Contribution of prednisone to the effectiveness of hexamethylmelamine in multiple myeloma.

The Eastern Cooperative Oncology Group evaluated hexamethylmelamine in 89 patients with advanced refractory or relapsing multiple myeloma. Hexamethylmelamine was initially used as a single agent administered orally at 200 mg/m2/day for the first 3 weeks of each 4-week cycle. When this regimen proved to be ineffective, it was modified first by increasing the dose of hexamethylmelamine to 280 mg/m2/day and subsequently by adding prednisone at 75 mg for the first 7 days of each 28-day cycle. None of the 39 patients receiving hexamethylmelamine without prednisone had an objective response, while two patients had minimal objective improvement (25%-50% decrease in M protein with symptomatic improvement). Only 14% of these patients had objective or symptomatic response or both. In contrast, patients treated with hexamethylmelamine plus prednisone had a 22% objective response rate, with another 14% showing lesser degrees of objective improvement. Fifty-one percent of the patients treated with this regimen had either objective or symptomatic improvement or both. Severe (grade 3) toxicity was seen in nearly two-thirds of the patients on the higher-dose hexamethylmelamine regimens compared with 37% of the patients receiving low-dose hexamethylmelamine; however, in most instances this represented rapidly reversible cytopenias. Because all but one of the patients responding to hexamethylmelamine plus prednisone had experienced previous treatment failure on regimens containing prednisone in similar dose and schedules, it is unlikely that the responses are due to prednisone alone. Instead, this study suggests that the activity of hexamethylmelamine in multiple myeloma is dependent on the concomitant administration of prednisone and that the combination regimen appears to be synergistic.

Adult↗
PubMed1987

The application of dose intensity to problems in chemotherapy of ovarian and endometrial cancer.

An attempt was made using dose intensity to resolve some of the conflicting issues regarding chemotherapy in ovarian cancer and endometrial cancer. Analyses were done to determine if dose intensity correlates with outcome of first-line and salvage chemotherapy of advanced ovarian cancer and chemotherapy of advanced endometrial cancer. The concept of dose intensity was used to analyze the relative contributions of individual drugs, such as cyclophosphamide, hexamethylmelamine, Adriamycin (Adria Laboratories, Columbus, OH) and cisplatin to outcome, and to suggest how such drugs should be used in combination.

Altretamine↗
PubMed1988

The role of cytoreduction in ovarian cancer.

Whether or not cytoreduction improves the outlook of ovarian cancer patients is not yet clear from data from Literature. Maybe not the successful procedure itself, but the favourable tumor characteristics of these tumors determine the prognosis. New studies are necessary to define the role of surgery in the overall management of ovarian cancer more precisely. In this article a Dutch study is presented, to answer the question about the influence of attempted cytoreductive surgery prior to, during chemotherapy on survival time and remission rates. All patients are treated with either combination chemotherapy and/or an attempt to cytoreduction prior to or during chemotherapy. With this strategy ethical problems concerning undertreatment are avoided. The study is currently activated but it is too early to draw any conclusions.

Altretamine↗
PubMed1988

The geometry of N-hydroxymethyl compounds. Part 2: Crystal structures of 1-(4-carbethoxyphenyl)-3-hydroxymethyl-3-methyltriazene, N-hydroxymethylpentamethylmelamine and N-hydroxymethylbenzamide.

Of the three N-hydroxymethyl compounds in the title, the first two have pronounced antineoplastic activity while the latter is biologically inactive. Crystals of the triazene have monoclinic symmetry with a = 8.540(1), b = 6.346(4), c = 22.460(5)A, beta = 98.75(2) degrees, and space group P21/c. The melamine forms disordered crystals of orthorhombic symmetry with a = 11.957(3), b = 17.267(3), c = 5.769(3)A. Of the symmetry elements in the observed space group Pnma, a mirror plane bisects the average molecule, implying that the hydroxymethyl group has equal probability of lying either side of this plane. Crystals of the benzamide show orthorhombic symmetry with a = 10.045(6), b = 7.763(3), c = 19.409(8)A, and space group Pbca. All three compounds are intermediates along biochemical demethylation pathways. The observed N-CH2OH distances, which are 1.469(5), 1.452(4), and 1.438(4)A respectively for the three compounds, correlate with the stability of this bond as measured by half-life. It is suggested that the correct degree of lability is important for biological activity, short strong bonds being too unreactive and excessively long ones being too unstable.

Altretamine↗
PubMed1988

Combined effects of host antitumor immune responses and chemotherapy. Studies with hexamethylmelamine.

The antitumor activity of hexamethylmelamine (HMM) was tested in various mouse tumor models in the presence or absence of host-vs-tumor graft responses. The drug was moderately active against Sarcoma-180 growing in different strains of non-sensitized mice. Strong protection was afforded when recipients were preimmunized with irradiated tumor cells 15 days before tumor challenge followed by HMM treatment. The drug did not show antitumor activity against two radiation-induced lymphomas of congenic mice of B10 background, inoculated into H-2 compatible hosts, or into mice incompatible for subregions of H-2. In this model HMM increased mortality of allogeneic mice presumably through impairment of host-vs-lymphoma graft resistance. In conclusion this study shows that synergistic or antagonistic effects can be obtained by combining chemotherapy with antitumor immune responses.

Altretamine↗
PubMed1985

First-pass metabolism of pentamethylmelamine in the rat liver.

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.

Altretamine↗
PubMed1985

[Research project of cancer chemotherapy].

Information exchange with regard to new antitumor agents has taken place through meetings dealing with various treatment areas within the US-Japan Cancer Research Program, contact between the National Cancer Institute (NCI) in the USA and the Cancer Chemotherapy Center, and meetings of the Early Clinical Trial Group of the EORTC. Cisplatin. VP16-213, 6-Thioguanine, DTIC and AMSA which were judged to be worth introducing to Japan from information obtained from the above sources were supplied by the NCI and clinical trials have been conducted. A joint study of advanced gastric cancer was conducted between the Northern California Oncology Group and a Japanese Cooperative Group involving 13 major institutions through the US-Japan Program. The study was meaningful for understanding the natural history of patients with gastric cancer in both countries.

Altretamine↗
PubMed1985

Pharmacokinetics of hexamethylmelamine administered via the Ip route in an oil emulsion vehicle.

Saline and Intralipid were compared as vehicles for the ip administration of hexamethylmelamine (HMM) in mice. The drug proved stable over at least 7 weeks in solution and 2 years in crystal form. Fiftyfold higher concentrations of HMM could be achieved in Intralipid than in saline. The peritoneal pharmacokinetics were first-order and linear over the concentration range of HMM in Intralipid from 50 to 2000 micrograms/ml. The mean peritoneal half-life of HMM in Intralipid was 12.5-fold greater than the mean half-life of HMM in saline at the same concentration. Peritoneal concentration X time drug exposure, as measured by the area under the curve in single-dose elimination experiments, was 1200-fold greater for HMM at 2000 micrograms/ml in Intralipid than at 50 micrograms/ml, near saturation, in saline. The steady-state peritoneal to plasma concentration ratios were 96-104 for HMM in Intralipid at concentrations of 300-2000 micrograms/ml, and the peritoneal concentration that could be maintained by the constant ip infusion of HMM at 2000 micrograms/ml in Intralipid was at least 1600-fold greater than that maintainable with HMM in saline. The mean peritoneal clearance calculated by two independent methods and at three different concentrations of HMM in Intralipid was 0.112 +/- 0.016 ml/minute. HMM in Intralipid is a stable formulation that can be used to increase peritoneal exposure to HMM and may potentially be used iv as well.

Altretamine↗
PubMed1985

Six-drug chemotherapy (hexamethylmelamine, doxorubicin, cisplatin, cyclophosphamide, methotrexate, and 5-FU; CHAMP-5) for ovarian carcinoma: alternating sequences of combination regimens.

Twenty-five patients with previously untreated adenocarcinoma of the ovary (International Federation of Gynecology and Obstetrics, stages II, III, and IV) were placed on a six-drug trial (CHAMP-5) for 18 months. This trial consisted of 28-day cycles of hexamethylmelamine, doxorubicin, and cisplatin alternating with hexamethylmelamine, cyclophosphamide, methotrexate, and 5-FU. After a minimum follow-up of 31 months, 14 (56%) of the 25 evaluable patients achieved complete or partial response and nine (36%) achieved complete pathologic response. Although CHAMP-5 is effective in the treatment of ovarian cancer, the results in these patients are not substantially different from those achieved with hexamethylmelamine, doxorubicin, and cisplatin alone.

Adenocarcinoma↗
PubMed1985

Phase II trials of hexamethylmelamine, dianhydrogalactitol, razoxane, and beta-2'-deoxythioguanosine as single agents against advanced measurable tumors of the pancreas. Gastrointestinal Tumor Study Group.

Phase II trials of several single agents demonstrated only minimal objective response rates in patients with pancreatic carcinoma and measurable tumors: hexamethylmelamine (7%; four responses among 55 patients); dianhydrogalactitol (2.5%; one response among 40 patients); razoxane (7%; two responses among 29 patients); and beta-2'-deoxythioguanosine (6%; two responses among 32 patients). Among patients with a good performance status (0-2) and no prior chemotherapy, response rates were 8% for hexamethylmelamine (two responses among 26 patients); 8% for dianhydrogalactitol (one response among 13 patients); 8% for razoxane (one response among 12 patients); and 10% for beta-2'-deoxythioguanosine (two responses among 20 patients). None of these agents given by the methods of this study offers substantive benefit to the patient with advanced pancreatic cancer.

Adenocarcinoma↗
PubMed1985

Response of ovarian cancer to combined cytotoxic agents in the subrenal capsule assay: Part I.

The subrenal capsule assay in normal immunocompetent mice was used to test the responsiveness of ovarian cancer to combination chemotherapy. Of the assays, 42 were of untreated tumors and 19 of previously treated tumors. Fifty-nine (97%) of the assays were evaluable. The previously treated tumors were less sensitive than the untreated ones. Of the treated tumors 44% were sensitive, 33% intermediately sensitive, and 22% resistant versus 56, 44, and 0%, respectively, of the untreated tumors (P less than .01). Repeat assays for the tumors of seven patients were performed successfully after five to eight courses of therapy with the combination of doxorubicin, cyclophosphamide, and cisplatin. The responsiveness to this combination had weakened significantly (P less than .01); the response of only one tumor remained unchanged. The rates of resistance to the drug combinations doxorubicin-cyclophosphamide-cisplatin, doxorubicin-cyclophosphamide-tegafur, and cyclophosphamide-vincristine were 11, 10, and 21%, respectively; there was, however, considerable interindividual variation in tumor responses to these combinations. Of other combinations, hexamethylmelamine combined with 4-epidoxorubicin, aclarubicin, or chlorambucil and cisplatin had effect, whereas the combinations of cisplatin and etoposide and of tegafur and methotrexate or mitomycin were quite ineffective, as measured by the assay. The reliability of the subrenal capsule assay in normal immunocompetent mice is discussed, and it is concluded that the assay can be used to assess the response of ovarian cancer to chemotherapy, including multidrug therapy, without routine histologic control.

Aclarubicin↗
PubMed1985

Comparison of cyclophosphamide plus cisplatin versus hexamethylmelamine, cyclophosphamide, doxorubicin, and cisplatin in combination as initial chemotherapy for stage III and IV ovarian carcinomas.

Among 187 women with stage III and IV ovarian carcinoma who participated in this comparative clinical trial, 181 were eligible for analysis. Of these patients, 89 received monthly treatment with CP [cyclophosphamide (1 g/m2) plus cisplatin (60 mg/m2)] and 92 received monthly treatment with HCAP [hexamethylmelamine (150 mg/m2/day X 7), cyclophosphamide (400 mg/m2), doxorubicin (30 mg/m2), and cisplatin (60 mg/m2)]. All treatments were administered iv on Day 1 of each monthly treatment cycle, except for hexamethylmelamine, which was administered orally on Days 2-8. With a median follow-up time of 30 months, survival curves for the two treatment groups were almost identical, as were their times to progression [estimated median survival, 24.6 months (Kaplan-Meier)]. Patient characteristics which significantly influenced survival were age, degree of histologic differentiation, extent of residual disease, stage of disease, and histologic type. Results of posttreatment laparotomies have been equal for the two treatment groups. Toxic effects of the two regimens have been similar, except for more frequent, more severe, and earlier neurotoxicity among patients treated with HCAP. Of the two regimens, CP has the better therapeutic index.

Adult↗
PubMedDate not supplied

Chemotherapy of human tumors in T-lymphocyte-deficient mice.

Human lung, ovarian, colonic, and renal carcinomas have been grown in mice artificially deprived of T-lymphocytes. All grew slowly and were shown to have a human karyotype even after several transplant generations. Their responses to chemotherapy were similar to the expected clinical response with the important exception of hexamethylmelamine which caused complete regression of two lung carcinomas (even when weighing up to 2.5 g at the start of treatment) and a renal carcinoma, while completely inhibiting the growth of an ovarian carcinoma and another lung carcinoma. Measurement of plasma carcinoembryonic antigen levels proved to be of value in assessing drug efficacy.

Altretamine↗