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At least 145 records · Page 8Linked to original sources
PubMed1983

Carbinolamines and related structures--potential alkylating metabolites of clinically active anticancer drugs.

The precise biochemical mechanism by which a number of clinically-active anticancer compounds function remains unclear. Among these are procarbazine (NSC-77213), cyclophosphamide (NSC-26271), streptozotocin (NSC-85998), dacarbazine (NSC-45388), and hexamethylmelamine (NSC-13875). In all cases, there is an N-methyl or N-alkyl substituent which can be or has been shown to generate carbinolamine-like intermediates as a result of oxidative metabolism. Such intermediates can react with amines, imines, sulfhydryls and similar functional groups to form covalent linkages. Thus, carbinolamine metabolites of these clinically-active compounds are proposed as the active agents capable of altering covalently nucleic acids and proteins. It is this alkylating property that may be responsible for these compounds adversely effecting the mitosis of neoplastic cells. Thus, a unifying hypothesis is proposed whereby metabolic hydroxylation of various miscellaneous anticancer agents is the basis for biological activity. In essence, therefore, three broad classes of alkylating agents may be perceived: (1) the classical alkylators such as the nitrogen and sulfur mustards and the sulfonates, (2) bioreductive alkylating agents, and (3) biooxidative alkylating agents such as the carbinolamines. Though the chemical spectrum of each category may be highly diverse, nevertheless, all function as alkylating agents.

Alkylating Agents↗
PubMed1983

Rapid formation of N-hydroxymethylpentamethylmelamine by mitochondria from rat small intestinal epithelium.

Isolated rat intestinal mitochondria showed a considerable capacity to convert hexamethylmelamine to its monodemethylated metabolite pentamethylmelamine. Mitochondrial turnover rate is about the same as compared with microsomal preparations. Only in mitochondrial incubations N-hydroxymethylpentamethylmelamine could be identified as a metabolic intermediate. The known chemical reactivity of carbinolamines means that this activation pathway in mitochondria could be involved in the pharmacological or toxic effects of hexamethylmelamine.

Altretamine↗
PubMed1984

Reproduction and teratology studies on hexamethylmelamine in the rat and rabbit.

The antineoplastic drug hexamethylmelamine (HMM) was evaluated for effects on reproduction and postnatal development in the rat and on embryonal and fetal development in the rat and rabbit. Daily po treatment of male rats for 62 days with doses of 0, 10, 20, or 40 mg/kg/day resulted in testicular atrophy, reduced fertility, and a possible dominant lethal mutagenic effect at the higher two dose levels. Alterations in morphology and function of the beta cells of the pancreatic islets were observed after treatment of males for more than 28 days with 20 or 40 mg/kg/day. The same dose levels administered to female rats for 14 days prior to breeding and through Day 13 or 20 of gestation had no adverse effects on fertility, but the highest dose was embryocidal and postnatal survival was decreased at both the 20- and 40-mg/kg/day dose levels. Similar effects on postnatal survival were observed when the drug was administered by gavage to rats during the last week of gestation and throughout the lactation period. Treatment of pregnant rats throughout organogenesis (Days 6 to 15) or for 4-day intervals during organogenesis (Days 6 to 9, 9 to 12, or 12 to 15) with po doses ranging from 20 to 80 mg/kg/day resulted in decreased body weight gain and food consumption, an increased resorption rate in dams receiving 80 mg/kg/day on Days 6 to 9, and decreased fetal weights at all dose levels and most treatment intervals. The incidence of minor skeletal defects was increased among litters of HMM-treated groups. Major fetal malformations were limited in number but were considered treatment related. Treatment of pregnant rabbits po on Days 6 to 18 of gestation with doses of 0, 20, 40, or 60 mg/kg/day did not result in an embryocidal or teratogenic effect. Treatment with 60 mg/kg/day did, however, result in decreased kit weights, indicating a mild embryo-fetotoxic effect.

Abnormalities, Drug-Induced↗
PubMed1984

Pancreatic beta cell vacuolation in rats after oral administration of hexamethylmelamine.

The effects of hexamethylmelamine (HMM) on morphology and function of the endocrine pancreas were investigated following the induction of a diabetic-like syndrome in a reproduction study in rats. Doses of 0, 20, 40, or 80 mg/kg/day were administered once daily, by gavage, to groups of 10 male and 10 female Sprague-Dawley rats for up to 77 days. Signs of toxicity were observed at all treatment levels and were of such severity at 80 mg/kg/day that this group was terminated after 8 days of treatment. Measurement of serum glucose levels revealed a dose- and time-related hyperglycemia in rats from the 20- and 40-mg/kg/day groups with levels exceeding 700 mg/dl in some rats after 77 days of treatment. Reversal of the hyperglycemia after discontinuing treatment with HMM occurred in some rats receiving 20 mg/kg/day, whereas the effects of higher doses were still present following a 2-month recovery period. Microscopically, there were hydropic degeneration of renal tubular epithelium and vacuolation of pancreatic beta cells. Ultrastructurally, vesiculation of the Golgi-smooth membrane reticular complex and a marked reduction in the number of insulin granules were observed. It appeared that HMM exerted a disruptive effect on the production of insulin at or prior to the level of the Golgi complex. The severity and time course of morphologic changes and hyperglycemia were dependent on dose and duration of treatment.

Administration, Oral↗
PubMed1983

A prospective randomized clinical trial of melphalan and cis-platinum versus hexamethylmelamine, adriamycin, and cyclophosphamide in advanced ovarian cancer.

From May 1978 until November 1980, 169 previously untreated patients with advanced epithelial ovarian cancer were entered into a prospective randomized clinical trial comparing the combination of hexamethylmelamine, Adriamycin, and cyclophosphamide (HAC) to a combination of melphalan and cis-platinum. Eleven patients were excluded from analysis and another 5 patients were excluded from response analysis. Of 153 patients evaluable for response, there were 47, or 30.7%, complete responders (all determined surgically), 6 partial responders, and 100 nonresponders. The response rate for the HAC group was 31% and for the melphalan-platinum group was 37.8%. The overall response rate was 34.6%. Residual tumor diameter (less than or greater than 2 cm) exerted a statistically significant effect on response--47.8 vs 24.4%. Of the 47 complete responders, 7, or 14.9%, have relapsed, with the median duration of remission of 44+ months. Of the 158 patients evaluable for survival, 90 patients have died, with a median survival time of 27.9 months (HAC = 26.4 months, melphalan-platinum = 29.6 months). Age, FIGO stage, histologic grade, and residual disease all exerted a significant effect on survival time. Second-line therapy in the treatment failures was of no benefit. Hematologic toxicity was greater in the melphalan-platinum group. Gastrointestinal toxicity was severe in both groups. Other toxicities were minor and infrequent.

Adult↗
PubMed1984

Failure of hexamethylmelamine as salvage therapy in ovarian epithelial adenocarcinoma resistant to combination chemotherapy.

Favorable responses to hexamethylmelamine (HMM) have been documented in untreated as well as in alkylating agent-resistant ovarian epithelial adenocarcinoma (OvCa). Platinum-based combination therapy for OvCa has been used since 1976. Eighteen patients with OvCa were treated with HMM as salvage therapy between February 1979 and October 1981. All patients had histologically confirmed OvCa. Eleven tumors were grade III/III and seven tumors were grade II/III. Sixteen patients had received cisplatin-based combination therapy, whereas two had received doxorubicin/cyclophosphamide because of other medical conditions. HMM was used alone in 16 patients and in combination with other drugs in two patients. The initial dose of HMM was 300 mg/m2/day X 14 days when used alone and 130 mg/m2/day X 14 days when used in combination with other drugs. Six patients were treated at a reduced initial dose because of prior marrow toxicity. Adverse effects were tolerable, with 14 patients experiencing hematologic toxicity (5 mild, 5 moderate, 3 severe, 1 life threatening) and 15 patients experiencing GI toxicity (5 mild, 7 moderate, 3 severe). Only 2 patients experienced no toxicity. No objective tumor responses were observed. Four patients had progression of tumor within 4 weeks of starting therapy and 14 patients had stable disease with a mean progression-free interval of 21 weeks. Although HMM is an active drug in untreated and alkylating agent-resistant OvCa, experience suggests that HMM at the dose and schedule tested has insignificant activity in patients who have failed cisplatin-based combination therapy.

Adenocarcinoma↗
PubMed1984

The effect of chemotherapy on lymphocyte subpopulations and cell-mediated cytotoxicity in patients with ovarian carcinoma.

Chemotherapy using adriamycin with cyclophosphamide, and cyclophosphamide with hexamethylmelamine or with alkeran causes no significant reduction in the total lymphocyte count, in the percentage subpopulations of T cells and B cells or in mononuclear cell cytotoxicity in patients with Stage II carcinoma of the ovary during their first course of chemotherapy.

Altretamine↗
PubMed1985

Mullerian inhibiting substance reduction of colony growth of human gynecologic cancers in a stem cell assay.

Mullerian Inhibiting Substance (MIS), a fetal testicular product that causes regression of the Mullerian duct in the male mammalian embryo, was evaluated for its antitumor effect on the premise that a substance active against this genital precursor in the fetus might also be active against tumors derived from these tissues. Increasingly pure fractions of biologically active MIS, prepared from newborn calf testes, were tested in the soft agar colony inhibition assay against single cell suspensions of fresh tumors derived in ascitic or solid form from patients with gynecologic malignancies. Twenty-eight tumor specimens placed in soft agar culture have provided sufficient growth to assess an MIS effect. Twenty-five of these 28 tumors showed significant colony inhibition after incubation with MIS. Increased antitumor response correlated with increased purification of MIS when the same tumor was treated with preparations of different purity. Samples obtained from the same patient at different times, from both ascites and solid tumor sources, produced nearly identical responses to MIS. MIS preparations, previously shown to be active in microcytotoxicity and colony inhibition assays against established human ovarian and endometrial carcinoma lines demonstrate consistent antitumor activity against fresh human gynecologic cancers removed at surgery.

Adenocarcinoma↗
PubMed1985

Hexamethylmelamine, methotrexate and 5-fluorouracil (HMF) for progressive ovarian carcinoma during therapy with cis-platinum, cyclophosphamide +/- doxorubicin.

Hexamethylmelamine, methotrexate, and 5-fluorouracil (HMF) is a second-line chemotherapy for patients with ovarian carcinoma refractory to platinum-based regimens. Two of 15 patients with tumor progression treated with HMF alone had objective complete responses while one had a 12-month disease-free interval (DFI). Among 8 patients treated with HMF and either intraperitoneal chromic phosphate and/or alternating platinum-based chemotherapy following second-look surgery which documented persistent carcinoma, 3 have experienced disease-free intervals of 19, 27, and 42 months. However, no one has been cured or had a long-term remission after HMF therapy alone.

Adult↗