Teniposide in refractory ovarian cancer: a phase II study.
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Adult↗
Biomedical subjects
M D'Incalci
Publications and source records attributed to M D'Incalci.
Metabolism of the anticancer agent 1-(4-acetylphenyl)-3,3-dimethyltriazene.
High pressure liquid chromatography was used in combination with mass spectrometry to confirm that the main products of in vitro metabolism of 1-(4-acetylphenyl)-3,3-dimethyltriazene are 1-(4-acetylphenyl-3-methyltriazene and 4-aminoacetophenone. In addition a novel metabolite, 1-[4-(1-hydroxyethyl)-phenyl]-3,3-dimethyltriazene, possessing antitumour activity similar to the parent drug, was identified.
Animals↗
Flow-cytometric analysis of DNA distribution after VP16-213 treatment of Lewis lung carcinoma.
The two dosage schedules of VP16 that gave the least and the greatest efficacy in Lewis lung carcinoma of the mouse were selected for evaluation of the cytokinetic effects observable in vivo at different intervals after treatment (schedule A: 40 mg/kg IV, on day 8 after transplant; schedule B: 13 mg/kg IV, repeated on days 8, 11, and 14 after transplant). After the single dose and after each repeated dose there was a marked increase in the percentage of cells in the LS-G2-M phases, with a corresponding decrease in the percentage of cells in G0-G1. The number of neoplastic tetraploid cells compared with normal diploid cells in the tumor was reduced after the single IV dose, and more markedly so after repeated doses. This study suggests that the more marked delay of cancer cell growth and greater effectiveness observed with schedule B is related to repeated blockage of the LS-G2-M phases.
Animals↗
Lack of activity of cyclophosphamide in ovarian cancer patients refractory to cis-dichlorodiammine platinum.
Twenty-three ovarian cancer patients refractory to first-line chemotherapy consisting of cis-dichlorodiamminoplatinum used as a single agent (50 mg/m2 IV every 4 weeks) were admitted to this study. They received cyclophosphamide as an IV push at a dose of 1 g/m2 every 3 weeks. They were evaluable for response after at least two cycles. None of the 18 evaluable patients responded: 15 (83%) showed rapid progression and three (17%) no change. Except in one case of severe leukopenia hematological toxicity was acceptable. Some (30%) of the patients experienced intractable vomiting on the day of cyclophosphamide administration.
Adult↗
Distribution, metabolism, and irreversible binding of hexamethylmelamine in mice bearing ovarian carcinoma.
The covalent binding of hexamethylmelamine (HMM) and its metabolites was studied in liver, tumor, blood, kidney, spleen, lung, brain, heart, and small intestine after a single IP injection of 2,4,6-14C-hexamethylmelamine (50 mg/kg) to C57Bl/6J female mice bearing 20-day-old M5076/73A ovarian cancer. Covalent binding to tissue macromolecules was measured 2, 10, and 40 h after injection of the drug. At 2 h liver and small intestine showed the highest levels of irreversibly bound metabolites, the lowest being found in brain and heart. Except in the small intestine, where a decrease was observed between 2 and 10 h, the level of covalent binding was constant up to 40 h. HMM metabolism was also studied. Tissue distribution of pentamethylmelamine (PMM), 2,2,4,6-tetramethylmelamine (TMM), and 2,4,6-trimethylmelamine (TriMM) was determined at the three times considered. At 2 h the drug was already extensively metabolized, TriMM being the major metabolite among those determined.
Altretamine↗
ICRF 159 plus radiation versus radiation therapy alone in cervical carcinoma. A double-blind study.
In a double-blind trial the effect of ICRF 159 or placebo associated with radiotherapy was compared in 70 patients with cervical carcinoma. No significant differences were found on histopathological examination of surgical specimens obtained 6 weeks after the end of the treatment. Clinical evaluation after a follow-up of 46 +/- 5 months, also showed no significant effect of ICRF 159 with radiotherapy.
Carcinoma, Squamous Cell↗
Ovarian reticular cell sarcoma of the mouse (M5076) made resistant to cyclophosphamide.
Resistance of mouse M5076 (M5) ovarian reticular cell sarcoma to cyclophosphamide (CTX) was obtained in vivo by repeated drug treatment followed by transplantation of the regrowing tumor. After 16 passages, we obtained an M5 subline resistant to CTX (M5-CTX-16R). Median survival times were approximately 29 and 39 days for M5 and M5-CTX-16R, respectively. Survival of M5-bearing mice given a single i.p. dose of 200 or 300 mg/kg was 160 and 168% of controls, respectively, whereas in M5-CTX-16R it ws 103 and 123%, respectively. The resistance was not reversible after 14 additional passages with no further CTX treatment. M5 and M5-CTX-16R appear similar in histological features, pattern of metastasis formation, and DNA content, as assessed by flow cytometry (hypotetraploid). Metastases of M5-CTX-16R were also resistant to CTX. Flow cytometry studies 12 and 24 hr after CTX treatment revealed a block in S and G2-M phases in both tumors. After 48 hr and at subsequent times, no cytokinetic pertubation was evident in M5-CTX-16R, whereas in M5 marked accumulation of cells in G2-M was observed at 48, 72, 96, and 120 hr. Cross-resistance was found between CTX, L-phenylalanine mustard, chlorambucil, and hexamethylmelamine. M5-CTX-16R was sensitive, but less so than M5, to cis-platinum, 1,3-bis(2-chloroethyl)-1-nitrosourea, and imidazole-4-carboxamide,5-(3,3-dimethyl-1-triazene). Adriamycin was equally active on M5 and M5-CTX-16R, while 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidine-beta-D-glucopyranoside) was inactive. This model appears to be suitable for studies on the mechanism of resistance to CTX and alkylating agents and for screening new, non-cross-resistant drugs.
Animals↗
Activity and pharmacokinetics of teniposide in Lewis lung carcinoma-bearing mice.
The antitumor activity of teniposide (VM26) was investigated in Lewis lung carcinoma (3LL) of the mouse after a single dose of 20 mg/kg iv (given 8 or 14 days after tumor transplant) or after three doses of 6.5 mg/kg iv (given on Days 8, 11, and 14 after tumor transplant) (total dose, 19.5 mg/kg). The single dose resulted in only 25% primary tumor reduction but had marked antimetastatic activity. The repeated doses (6.5 mg/kg x 3) were much more effective, with 85% primary tumor reduction and the apparent disappearance of all metastatic deposits. The pharmacokinetics of VM26 was investigated in 3LL-bearing mice by a high-performance liquid chromatographic assay. At both of the above doses VM26 disappeared from mouse plasma biphasically, with an elimination half-life of about 70 mins. The concentrations in metastases were higher than in primary tumor, where very low levels were found. The highest VM26 levels were found in liver, small intestine, and kidney, and the lowest levels were found in the brain. Excretion of VM26 in urine amounted to less than 5% of the dose.
Animals↗
Studies of the mode of action of antitumour triazenes and triazines--IV. The metabolism of 1-(4-acetylphenyl)-3,3-dimethyltriazene.
The metabolism of 1-(4-acetylphenyl)-3,3-dimethyltriazene has been studied in vivo and in vitro in mice. This dimethyltriazene was extensively metabolised in vivo and HPLC analysis of the plasma revealed the presence of two metabolites, the monomethyltriazene, 1-(4-acetylphenyl)-3-methyltriazene, and the arylamine, 4-aminoacetophenone. The dimethyltriazene was also biotransformed in vitro by a 9000 g fraction of mouse liver homogenate to products which were selectively toxic to TLX5 lymphoma cells. HPLC analysis of the products of in vitro metabolism under these conditions showed the presence of the monomethyltriazene but in an amount insufficient to account for the observed cytotoxicity. The monomethyltriazene was itself rapidly biotransformed by a 9000 g fraction of mouse liver homogenate, and by isolated mouse hepatocytes.
Animals↗
Studies of the mode of action of antitumour triazenes and triazines-III. Metabolism studies on hexamethylmelamine.
These is good evidence that the antitumour agent hexamethylmelamine (HMM) undergoes oxidative metabolic activation which might occur in the liver and/or extrahepatically. The hepatic microsomal N-methylmelamine metabolizing enzymes were investigated in mice and exhibited different affinities for different melamine derivatives. The apparent Km values are 0.09 mM for HMM, 0.23 mM for pentamethylmelamine, 0.91 mM for 2,2,4,6-tetramethylmelamine and 1.7 mM for trimethylmelamine. HMM inhibited its own metabolism in vitro at substrate concentrations greater than 0.05 mM. Its hepatic microsomal N-demethylation rate was reduced when the mice were pretreated with the hepatic glutathione depleting agent methyliodide. Injection of hexaethylmelamine, a derivative of HMM without antineoplastic properties against the M5076 sarcoma in mice, lead to plasma concentrations of drug and metabolite pentaethylmelamine which were only a fraction of the drug and metabolite levels achieved after a similar dose of HMM.
Altretamine↗
Pharmacokinetics of VP16-213 in Lewis lung carcinoma bearing mice.
The pharmacokinetics of VP16 have been investigated in Lewis lung bearing mice after i.v. doses of 13 and 40 mg/kg. At both doses the plasma elimination of half-life was around 30 min. The lowest VP16-213 levels were in brain and primary tumor. Drug concentrations were much higher in metastases than in primary tumor. The highest concentrations were in small intestine, liver and kidney. Drug levels in the liver were disproportionally higher after 40 mg/kg, and AUC value being approximately 12 times greater than after 13 mg/kg. Urinary excretion of VP16-213 as unchanged drug accounted for 20-30% of the administrated dose in the 60 h after treatment. The concentration cytotoxicity curve was very steep and apparently similar for cells derived from primary tumor or metastases grown in vitro.
Animals↗
Pharmacokinetics of VP16-213 given by different administration methods.
Plasma pharmacokinetics of VP16-213 were investigated after a 30-60 min infusion in 14 adult patients and six children. In adult the elimination half-life (T1/2 beta), plasma clearance (Clp) and volume of distribution (Vd) were respectively 7.05 +/- 0.67 h, 26.8 +1- 2.4 ml/min/m2, and 15.7 +1- 1.8 l/m2; in children 3.37 +/- 0.5 h, 39.34 +1- 6.6 ml/min m2, and 9.97 +/- 3.7 l/m2. After repeated daily doses no accumulation of VP16-213 was found in plasma. The unchanged drug found in the 24 h urine after administration amounted to 20-30% of the dose. In eight choriocarcinoma patients plasma levels of VP16-213 were measured after oral capsules and drinkable ampoules. The bioavailability compared to the i.v. route was variable, mean values being 57% for capsules and 91% for ampoules. In one further patient, with abnormal d-Xylose absorption results, VP16-213 was not detectable in plasma after the oral ampoule dose. Steady state levels investigated in three patients after 72 h continuous VP16-213 infusion (100 mg/m2/24h) were around 2-5 micrograms/ml. Levels of VP16-213 were undetectable in CSF after i.v. or oral administration.
Administration, Oral↗
In vitro cytotoxicity of VP 16 on primary tumor and metastasis of Lewis lung carcinoma.
VP 16 activity was investigated on cells derived from primary tumor or metastases of Lewis lung carcinoma grown in vitro. After 24 hr exposure to VP 16 we found a marginal effect at 0.1 microgram/ml, but at 1 and 10 microgram/ml [3H]-TdR uptake was 37 and 85% less than controls for primary tumor and 43 and 83% for metastases; cell numbers dropped to 41 and 76% of controls for primary tumor and 30 and 68% for metastases. After 72 hr exposure VP 16 had a similar effect on cells of primary tumor or metastases, but a cytotoxic effect was already evident at 0.01 microgram/ml and increased proportionally to the concentration reaching virtual complete cell killing at 1 microgram/ml. This study suggests that the much greater in vivo sensitivity to VP 16 of metastases than primary tumor of Lewis lung carcinoma probably arises less from an intrinsically greater susceptibility of metastatic cells than from pharmacokinetic factors.
Animals↗
Routes of elimination of hexamethylmelamine and pentamethylmelamine in the rat.
1. In the rat 40% of a dose of 25 mg/kg of hexamethylmelamine or pentamethylmelamine was excreted in the urine as metabolites, more than 95% of which were N2N4-dimethylmelamine and monomethylmelamine. 2. Biliary excretion of hexamethylmelamine or pentamethylmelamine and their N-demethylated metabolites accounted for less than 2% of the administered dose. Only 0 X 3% was excreted with the faeces, suggesting that there is intestinal reabsorption of a portion of the methylmelamines passing into the bile. 3. Conjugates of methylmelamines with glucuronic acid or sulphate were found only in minute quantities in the urine or bile of rats treated with hexamethylmelamine or pentamethylmelamine. However a conjugation product of pentamethylmelamine, of as yet unknown nature, is a major metabolite after pentamethylmelamine treatment.
Altretamine↗
Activity of 1-p-(3,3-dimethyl-1-triazeno) benzoic acid potassium salt in M 5076/73A ovarian reticular cell sarcoma of the mouse.
1-p-(3,3-dimethyl-1-triazeno) benzoic acid potassium salt (DM-COOK) was tested on M 5076/73A (M5) mouse sarcoma at a dose of 40 or 50 mg/kg/day (Days 6--14) after im transplant of 7 x 10(5) cells, with or without surgical removal of the primary tumor on Day 14. Treatment at either dose level resulted in reduction of the primary tumor weight to around 50% of that in the controls, and striking antimetastatic effects were observed. When a dose of 40 or 50 mg/kg of DM-COOK was followed by surgery, there were 14% and 40% long-term survivors, respectively, but the higher dose caused about 30% toxic deaths. After iv injection of 10(3) or 10(5) M5 tumor cells, no artificial metastases appeared in DM-COOK-treated mice, whereas all control animals had metastatic involvement in the liver, spleen, ovaries, and kidneys.
Animals↗
Hexamethylmelamine and pentamethylmelamine tissue distribution in M5076/73A ovarian cancer-bearing mice.
The distribution of hexamethylmelamine (HMM), pentamethylmelamine (PMM), and their metabolites N2,N2,N4,N6-tetramethylmelamine (TMM) and N2,N4,N6-trimethylmelamine (TriMM) was investigated in different tissues of M5076/73A ovarian cancer-bearing mice given 100 mg/kg ip of either drug. The area-under-the-curve (AUC) values of HMM and PMM, expressed in microgram/g x min after these drug treatments, were 2432 and 1296 in tumor, 6290 and 8141 in liver, 9779 and 21,294 in spleen, 6840 and 10,800 in kidney, 4003 and 4295 in heart, 1569 and 1327 in brain, 163,689 and 50,809 in adipose tissue, 88,725 and 45,070 in lymph nodes, 15,033 and 18,992 in small intestine, and 393 and 351 in plasma, respectively. The elimination rate of HMM for the different organs was similar, with a half-life of 37-48 mins; PMM disappeared with more variability, the half-life being 19-46 mins. While TMM concentrations were not very different from those of HMM or PMM, TriMM was much higher in all organs evaluated, particularly the brain, where AUC values were 21-24 times those of the administered drug.
Altretamine↗
Hexamethylmelamine distribution in patients with ovarian and other pelvic cancers.
The distribution of hexamethylmelamine (HMM) was investigated in surgical biopsies from 12 patients with pelvic cancer who were given an oral dose of 200 mg at 2-24 hours before the operation. The highest concentrations of HMM were found in tissues, such as omentum and subcutaneous tissue, that have a predominant lipidic component. HMM concentrations in the primary tumor were lower than in other tissues and were similar to those in plasma. HMM concentrations in metastases appeared to be higher than in the primary tumor, and in metastases with a diameter less than 3 mm, drug levels were two to ten times those in larger ones. Plotting the HMM concentrations versus time, utilizing the data from different patients, the elimination half-lives were found to be 9.05, 8.82, and 8.53 in plasma, tumor, and subcutaneous tissue, respectively.
Adipose Tissue↗
Hexamethylmelamine-CAF (cyclophosphamide, methotrexate, and 5-FU) and cisplatin-CAF in refractory ovarian cancer.
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Adult↗