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At least 235 records · Page 13Linked to original sources
PubMed1987

Platinum-DNA adducts in leukocyte DNA correlate with disease response in ovarian cancer patients receiving platinum-based chemotherapy.

Fifty-five ovarian cancer patients receiving platinum drug-based chemotherapy have been studied prospectively to determine the extent of formation of the bidentate intrastrand adducts of diammineplatinum covalently attached to the N7 positions of adenosine and/or guanosine in leukocyte DNA. Data for clinical response, obtained from medical records, were then correlated with the adduct values. Patients were treated with platinum-based single-agent or combination chemotherapy containing cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum on approved experimental protocols. Adduct measurements were performed by ELISA, and disease response to therapy was assessed by standard oncologic criteria. This study comprises a total of 101 blood samples obtained after intravenous cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum infusion from 55 individuals, and in each case the highest (or "peak") adduct level for each patient was chosen for statistical analysis. Values for median adduct levels in patients grouped by complete response, partial response, and no response were 212, 193, and 62 amol of adduct per microgram of DNA, respectively. Analysis of these data by Jonckheere's test (an extension of the Mann-Whitney test) shows that higher levels of adduct formation correlates with disease response with a two-sided P value of 0.030. Of eight patients on single-agent therapy whose buffy-coat samples did not have measurable adduct levels, none responded to therapy. Analysis of these data using the exact test for trend shows that the formation of adduct at a level of 160 amol/micrograms of DNA or greater correlates with disease response with a two-sided P value of 0.032. Thus in ovarian cancer patients, the formation of the intrastrand diammineplatinum adducts in leukocyte DNA is associated with favorable disease response to cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum chemotherapy.

Adult↗
PubMedDate not supplied

Solvent, emulsifier and drug concentration factors in poly(D,L-lactic acid) microspheres containing hexamethylmelamine.

Biodegradable poly(D,L-lactic acid) (PLA) microspheres containing hexamethylmelamine (HMM) were developed for potential use in chemoembolization and intraperitoneal implantation. The emulsion-solvent-evaporation/extraction method was used to prepare 15 formulations with different drug/polymer ratios, solvent compositions and emulsifer concentrations in the continuous aqueous phase. A central composite experimental design was used, with five levels of the three different factors. All formulations resulted in the formation of discrete matrix microspheres containing crystalline drug. The mean particle sizes of the microsphere formulations ranged from 62-348 microm and the effect of the independent variables on microsphere size was satisfactorily predicted using response surface methodology. For theoretical drug loads of 5-40%, efficiency of entrapment ranged from 75-107% and porosities of the microspheres were between 0-6.5%. The rate of drug release from the microspheres depended on drug loading and particle size. Microspheres with 22.5% or greater theoretical drug content released drug rapidly, with almost complete release occurring in 70 h or less. Formulations with drug loading of 5% and 9.57%, however, released drug very slowly, with less than 50% released in 40 days. Release kinetics of narrow sieve cuts of microspheres with high drug load (35.4%) followed square root of time profiles.

Altretamine↗
PubMed1995

Hexamethylmelamine is a potent inducer of deletions in male germ cells of Drosophila melanogaster.

Chemotherapy-related second tumors constitute a matter of concern in cancer treatment. Therefore, it is of great interest to elucidate the mechanisms by which cytostatic drugs exert their mutagenic and/or carcinogenic activity besides the anticancer effect and the possible relationship among them. A useful and informative approach to this problem is the analysis of the mutation spectra induced by these drugs in eukaryotic organisms. Sequence analysis of the mutations induced by hexamethylmelamine, a crosslinking agent extensively used in the treatment of ovarian cancer, in male germ cells of Drosophila was conducted using the v locus as reporter gene. Both intra-locus and multi-locus deletions were induced whereas based changes were almost absent. Thus, it is proposed that deletions are likely to be involved in the generation of second malignancies in hexamethylmelamine-treated patients. It has to be stressed that systems, such as v, capable of efficiently recovering mutations caused by big losses of DNA, should be used for the study of mutational spectra induced by cross-linking agents.

Altretamine↗
PubMed1990

Selecting drug combinations based on total equivalent dose (dose intensity)

We describe a mathematical model for selecting cytotoxic drugs and dosages for a combination regimen based on the antitumor activities of the drugs given as single agents and their organ-specific maximum tolerated doses. The regimen defined maximizes an approximate measure of antitumor effect subject to constraints on combined toxicity. This approach does not assume that the underlying dose-response curve is steep; nor does it assume that maximally dose-intense regimens are clinically appropriate in all situations. Whether the identified regimen is superior to standard treatments should be determined by prospective, randomized clinical trials. Determining which drugs to combine and in what proportions to combine them offers combinatorially huge numbers of possibilities. The method described here offers one approach to identifying combinations worthy of evaluation in prospective trials.

Altretamine↗
PubMed1990

A randomized study of sequential versus alternating combination chemotherapy in advanced ovarian carcinoma.

The concept of using either alternating or sequential combination chemotherapy with non-cross-resistant combinations was tested in a randomized trial including 301 previously untreated patients with advanced epithelial ovarian carcinoma. The sequential schedule consisted of CAF (cyclophosphamide, doxorubicin, 5-fluorouracil) followed by PH (cisplatin, hexamethylmelamine) in nonresponders, CAF- greater than PH (n = 157), and the alternating regimen consisted of CAF/PH (n = 144). With a median observation time of 54 months, no statistically significant differences were found between the pathologically complete response (PCR) rates of 17% and 16%, respectively, nor were there any statistical differences in median disease-free survival for PCR patients (CAF- greater than PH 34+ months and CAF/PH 26+ months), in overall survival (28 and 24 months, respectively), or in time to treatment failure (10 and 11 months). The overall estimated cure rate was 13%. An equal degree of myelosuppression was seen with the two regimens, whereas neuro- and nephrotoxicity were more pronounced when PH was given sequentially to CAF than with the alternating schedule. We conclude that the sequential and the alternated use of doxorubicin- and platinum-based regimens yield equivalent results and that other approaches should be investigated to improve treatment effects.

Adult↗
PubMed1984

Hexamethylmelamine in advanced head and neck cancer. A phase II study.

The results of hexamethylmelamine therapy in 20 patients with advanced squamous cell head and neck cancer are reported. No patient had previously received chemotherapy. The dose of hexamethylmelamine was 8 mg/kg/day p.o. There was partial response in 3/20 (15%) patients. The duration of the response was 6-10 weeks. Twelve of 20 (12/20) patients had stable disease for a median of 8 weeks (range: 4-18 weeks). Hexamethylmelamine was well tolerated with the only significant toxicity being mild nausea and vomiting. This drug deserves further evaluation in the treatment of head and neck cancer.

Aged↗
PubMed1984

Mitomycin-C, etoposide, cisplatin, and hexamethylmelamine (MEPH) as a second-line regimen in lung cancer.

Fifty-three patients with advanced lung cancer refractory to chemotherapy with MACC (methotrexate, adriamycin, cyclophosphamide, and CCNU) were treated with a combination of mitomycin-C, etoposide, cisplatin, and hexamethylmelamine (MEPH). Among 45 evaluable patients, there were seven partial responders (16%), including 2/18 adenocarcinomas, 3/13 small cell anaplastic carcinomas, 1/5 large cell anaplastic carcinomas, and 1/9 squamous cell carcinomas. Major toxic side effects included thrombocytopenia (30/45 patients), leukopenia (22/45 patients), and emesis. Renal toxicity occurred in three patients, and cardiac arrhythmia was observed in one patient. Despite a low response rate, which was expected in this group of heavily pretreated patients with poor prognostic characteristics, these data suggest a lack of cross-resistance between MEPH and MACC.

Altretamine↗
PubMed1985

Single agent vs. combination chemotherapy for ovarian cancer.

Forty evaluable patients with advanced epithelial cancers of the ovary received chemotherapy. Twenty-seven previously untreated patients underwent a 1:1 randomization between a combination of Cytoxan, Hexamethylmelamine, and Fluorouracil (CHF) versus a single agent, L-phenylalanine mustard (L-pam). Thirteen patients previously treated with other therapies received CHF as a second-line therapy. Eighty-five percent of the patients receiving triple therapy were responders, versus 57% in the single agent group. Fifty percent of the CHF group had a complete response versus 17% in the L-pam group (p = 0.09). All patients with complete resection of less than 2 cm residual disease at primary surgery were responders, regardless of the type of therapy. Response in these patients is defined in terms of disease-free interval. The importance of maximal surgical resection in management of these cancers is discussed. Five of eight patients treated with CHF undergoing second-look operations had no evidence of disease. One of three L-pam treated patients had no evidence of disease at second-look surgery. Six of 13 patients (46%) had partial response to CHF as a second-line drug.

Altretamine↗
PubMed1990

The role of hexamethylmelamine in the combination chemotherapy of advanced ovarian cancer: a comparison of hexamethylmelamine, cyclophosphamide, doxorubicin, and cisplatin (H-CAP) versus cyclophosphamide, doxorubicin, and cisplatin (CAP).

To evaluate the contribution of hexamethylmelamine (HMM) to the treatment of advanced ovarian cancer with combination chemotherapy, we compared the results of treatment with HMM, cyclophosphamide, doxorubicin, and cisplatin (H-CAP regimen) to treatment results using cyclophosphamide, doxorubicin, and cisplatin (CAP regimen). The treatment regimens were identical in dosage and schedule with the exception of the addition of HMM to one regimen. Fifty-five patients treated with H-CAP at Vanderbilt University Hospital between August 1977 and March 1980 were compared with a subsequent group of 22 patients who received CAP between October 1984 and October 1987. Following six months of therapy, patients were restaged either with second-look laparotomy or with clinical restaging. Fifty-three of 55 patients (96%) had objective responses to H-CAP compared with 14 of 21 patients (67%) treated with CAP (p = 0.001). The pathologic complete response rate was also higher in the patients who received H-CAP (35% versus 19%). The median survival of patients receiving H-CAP is 47 months compared to 21 months for the CAP patients. When patients with limited residual disease (maximum tumor diameter less than or equal to 3 cm) were compared, the median survival also favored the H-CAP treatment (101 months versus 21 months, p = 0.002). The median time to progression was also greater in patients receiving H-CAP versus those receiving CAP (67 months versus 16 months, p = 0.045). Treatment-related toxicity did not differ substantially between the two regimens. Our findings suggest that the addition of HMM to CAP chemotherapy prolongs the median survival in patients with ovarian cancer and limited residual disease following cytoreductive surgery.

Adult↗
PubMed1994

A randomized clinical trial in bronchogenic small-cell carcinoma evaluating alternating maintenance therapy of vincristine, adriamycin, procarbazine, and etoposide (VAPE) with cyclophosphamide, CCNU, and methotrexate (CCM) versus CCM maintenance alone in complete responders following VAPE induction and late intensification.

Initially, 109 evaluable patients with locally advanced or metastatic small cell lung cancer (SCLC) were treated with vincristine, Adriamycin, procarbazine, and etoposide (VAPE). Partial (PR) or nonresponders (NR) were crossed to CCM (cyclophosphamide, CCNU, and methotrexate) and then to HMiVe (hexamethylmelamine, mitomycin C, vinblastine) sequentially at maximum response. Complete responders (CR) were intensified by 50% with VAPE primarily and randomized to VAPE, alternating with CCM or CCM alone during maintenance. CR patients with limited disease received local thoracic irradiation and prophylactic cranial irradiation (PCI), whereas those with extensive disease received PCI alone. There were 45 patients (41%) who achieved a CR to chemotherapy, and 27 patients were eligible for randomization. Of 12 CR patients randomized to alternating therapy (VAPE/CCM), the median survival was 25.9 months compared to 12.9 months for 15 CR patients randomized to continuous CCM (P = .049). In addition, 35 patients achieved a PR (32%) and 29 were NR (27%). Overall median survivals were significantly different for the CR patients (13.0 months) as compared to PR (7.6 months) and NR patients (6.4 months). Late intensification did not appear to add substantially to survival while contributing to toxicity. In summary, VAPE is a new outpatient regimen for SCLC, which is highly effective as an induction regimen with moderate hematologic toxicity and predominantly gastrointestinal nonhematologic toxicity.

Aged↗
PubMed1986

Acute myelocytic leukemia in a patient treated with hexamethylmelamine.

This case report describes a 76-year-old white woman who was found to have ovarian cancer and underwent chemotherapy with hexamethylmelamine. After 34 months of therapy, she developed an acute myelocytic leukemia. Although commonly reported as a side effect of alkylating agents, this is believed to be the first reported case of an acute nonlymphocytic leukemia associated with hexamethylmelamine use.

Aged↗
PubMed1994

Advances in the chemotherapy of gynecologic cancer.

By combining paclitaxel and cisplatin in treatment schedules for the initial treatment of advanced ovarian cancer, new hope has been engendered that we can further improve survival. With premedication, paclitaxel can be administered safely as a short infusion. The combination of paclitaxel and carboplatin is recognized as an alternative to the combination of cisplatin and paclitaxel, and is now under study to define its role in future treatment programs. Other new drugs have been recognized as active in platinum-resistant disease, including docetaxel and gemcitabine. Renewed interest arose for a chronic low dose of oral etoposide in platinum-refractory ovarian cancer. The results obtained with chemotherapy in cervical cancer have always been modest, and no combinations have been shown to result in improved survival rates as compared with single drugs. The novel biologic regimen, using retinoids and interferon, was confirmed to be active in locally advanced cervical cancer. In trophoblastic disease, the Charing Cross scoring system is a relevant pretreatment scoring system compared with the International Federation of Gynecology of Obstetrics staging. Careful recognition of prognostic subgroups can prevent under- or overtreatment.

Altretamine↗
PubMed1982

Specific determination of pentamethylmelamine and its demethylated metabolites in human plasma by high pressure liquid chromatography.

Pentamethylmelamine (PMM) and its demethylated metabolites tetra-N2246, tri-N246 and tri-N224 have comparable relative antitumor potencies in animal systems. We have developed a sensitive and specific high pressure liquid chromatography (HPLC) assay for these compounds in the plasma of patients receiving pentamethylmelamine, a cytotoxic S-triazine derivative now undergoing clinical trials. The method involves analysis of an ethyl acetate extract of plasma by a high pressure liquid chromatograph containing a reverse-phase column and ultraviolet detection at 240 nm. The mobile phase is acetonitrile and KH2PO4 buffer (pH 5.5); gradient elution over 25 min yields relative retention times to hexamethylmelamine as internal standard of 0.36, 0.40, 0.54 and 0.70 for tri-N246, tri-N224, tetra-N2246 and PMM. The lower limit of sensitivity for each is 300 ng/ml. Pharmacokinetic studies on four patients receiving a 24-h infusion of PMM (doses 900-3000 mg/m2) showed a mean terminal half-life of PMM of 101 +/- 28 (SD) min, a mean volume of distribution of 2036 +/- 75 ml/kg, and a metabolic clearance rate of 14.2 +/- 3.7 (ml/min)/kg. Mean areas under the plasma-vs-time curves of tri-N246, tri-N224 and tetra-N2246 were 126%, 41% and 56% of PPM, demonstrating extensive formation of these metabolites in man.

Altretamine↗