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Therapeutic Drug Monitoring Dec 1997Blood samples from 34 recipients of kidney transplants who were on multidrug therapy including azathioprine were analyzed using two methods in parallel for red blood... (Comparative Study)
Comparative Study
Blood samples from 34 recipients of kidney transplants who were on multidrug therapy including azathioprine were analyzed using two methods in parallel for red blood cell (RBC) concentrations of methylated 6-mercaptopurine (6-MP) metabolites. Chemical hydrolysis with high-performance liquid chromatography (HPLC) showed values ranging from 0 to 20,259 pmol/8 x 10(8) RBCs, compared with enzymatic hydrolysis with HPLC that resulted in values ranging from 16 to 22,252 pmol/100 microl packed RBC. Results of the two methods were highly correlated; the coefficient of correlation (r) was equal to 0.93 (95% confidence interval [CI] = 0.87-0.97 [y = 1.12x + 187]). Within series imprecision was 3.1% compared with 6.3%, and between-run imprecision was 10.3% compared with 20.7%, for the enzymatic and chemical methods, respectively. The enzymatic method was found to be more specific and to save time and labor, but with the chemical method methylated metabolites and 6-thioguanine nucleotides (6-TGN), the main active metabolites of azathioprine and 6-MP, can be measured in the same run. The results indicate that methylated 6-MP metabolites mainly exist as ribonucleotides in RBCs.
Topics: Azathioprine; Chromatography, High Pressure Liquid; Erythrocytes; Humans; Hydrolysis; Kidney Transplantation; Mercaptopurine; Methylation; Methylthioinosine
PubMed: 9421108
DOI: 10.1097/00007691-199712000-00010 -
International Journal of Radiation... Dec 1997To evaluate the effects of biochemical modulation by N-(phosphonacetyl)-L-aspartate (PALA), 6-methylmercaptopurine riboside (MMPR), and 6-aminonicotinamide (6AN), (PALA...
PURPOSE
To evaluate the effects of biochemical modulation by N-(phosphonacetyl)-L-aspartate (PALA), 6-methylmercaptopurine riboside (MMPR), and 6-aminonicotinamide (6AN), (PALA + MMPR + 6AN is referred to as PMA) on tumor radiosensitivity, and evaluate the efficacy of the addition of 5-FU to the PMA + XRT regimen for enhancement of tumor response to radiation without exceeding normal tissue tolerance.
METHODS AND MATERIALS
A first generation transplant of the CD8F1 spontaneous murine tumor was studied. 31P nuclear magnetic resonance spectroscopy was used to determine the interval between chemotherapy and radiation based on energy depletion. PMA was administered three times with fractionated XRT (15 Gy x 3 = 45 Gy) on days 1, 10, or 11, and 21. The addition of 5-fluorouracil (5-FU) at maximum tolerated doses was evaluated and intergroup comparisons were made for tumor growth delay, local control, and disproportionate normal tissue damage.
RESULTS
The combination of 5-FU + XRT induced a tumor doubling time of 75.4 days (67.4-84.4) (p < 0.0001 compared to XRT), validating that in this tumor model, pretreatment with bolus i.p. 5-FU enhanced XRT. In comparison, mice treated with PMA + XRT had a tumor doubling time (TDT) > 123.2 days (109.4-138.7), (p < 0.0001 compared to 5-FU + XRT). The addition of 5-FU to PMA + XRT induced a doubling time of > 170.8 days (150.7-193.7) (p = 0.0002 compared to PMA + XRT). The doubling time for the PMA + XRT cohort and the PMA + 5-FU + XRT cohorts are underestimates since some of the tumor bearing mice continue to have a complete regression (CR). The CR rate (measured on day 250) for the PMA + 5-FU + XRT cohort was 31.7% compared to 0% for 5-FU + XRT and 10% for PMA + XRT (p < 0.05). Mortality and local effects induced by radiation in the PMA + XRT group were comparable to the toxicity for the PMA + 5-FU + XRT group indicating that the addition of 5-FU at 75 mg/kg to PMA + XRT was tolerated and induced both greater CR and tumor doubling times than XRT alone, 5-FU (150 mg/kg) + XRT, or PMA + XRT.
CONCLUSIONS
PMA is superior to 5-FU as a radiosensitizer in the schedule studied. The combination of PMA + 5-FU further enhanced XRT without exceeding normal tissue tolerance.
Topics: 6-Aminonicotinamide; Animals; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Cell Division; Combined Modality Therapy; Fluorouracil; Mammary Neoplasms, Animal; Methylthioinosine; Mice; Radiation-Sensitizing Agents; Radiotherapy Dosage; Time Factors
PubMed: 9392557
DOI: 10.1016/s0360-3016(97)00505-1 -
Gastroenterology Aug 1997
Topics: Antimetabolites; Antimetabolites, Antineoplastic; Azathioprine; Chromatography, High Pressure Liquid; Crohn Disease; Humans; Mercaptopurine; Methylthioinosine; Thioguanine
PubMed: 9247497
DOI: 10.1053/gast.1997.v113.agast971130690 -
Cancer Chemotherapy and Pharmacology 1997To elucidate the effect of methotrexate (MTX) on 6-mercaptopurine (6-MP) metabolism in rats.
PURPOSE
To elucidate the effect of methotrexate (MTX) on 6-mercaptopurine (6-MP) metabolism in rats.
METHODS
Fourteen rats were given 6-MP 20 mg/kg daily for 7 days. Seven of the rats were also given MTX 20 mg/kg on days 5 and 7. Blood samples were obtained from all rats on days 0.5 and 8, and red blood cell (RBC) lysates were analysed for thiopurine methyltransferase (TPMT) activity and the concentration of methylated 6-MP metabolites [methyl mercaptopurine ribonucleotides (MMPRP)] and 6-thioguanine nucleotides (6-TGN).
RESULTS
The concentration of MMPRP increased 2.4 times from day 5 to day 8 in RBCs from rats given MTX in addition to 6-MP, as against 1.2 times in rats given 6-MP alone (P = 0.003). 6-TGN levels increased and TPMT activity decreased from day 5 to day 8, with no difference between the 6-MP and the 6-MP plus MTX groups.
CONCLUSIONS
Single bolus doses of MTX increase the concentration of MMPRP in rats given daily s.c. doses of 6-MP, with no effect on 6-TGN concentration or TPMT activity.
Topics: Animals; Erythrocytes; Guanine Nucleotides; Male; Mercaptopurine; Methotrexate; Methylthioinosine; Methyltransferases; Nucleic Acid Synthesis Inhibitors; Rats; Rats, Wistar; Thionucleotides
PubMed: 9225958
DOI: 10.1007/s002800050672 -
Investigational New Drugs 1997The results of several clinical trials support the hypothesis that biochemical modulation may enhance the antitumor activity of 5-Fluorouracil (5-FU). We have performed... (Clinical Trial)
Clinical Trial
Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine ribonucleoside (MMPR), and leucovorin in patients with advanced cancer.
The results of several clinical trials support the hypothesis that biochemical modulation may enhance the antitumor activity of 5-Fluorouracil (5-FU). We have performed a phase I trial using a combination of three different biochemical modulators at the optimal dose established in previous clinical trials. The modulators include: phosphonacetyl-l-aspartate (PALA), which may increase 5-FU incorporation into RNA; leucovorin, which potentiates thymidylate synthase inhibition; and 6-methylmercaptopurine riboside (MMPR), which promotes the intracellular retention of fluorinated nucleotides. The treatment regimen consisted of PALA 250 mg/m2 day 1, followed 24 h later by MMPR 150 mg/m2 as an iv bolus, and the initiation of a 24-hour infusion of 5-FU along with leucovorin 50 mg/m2. This regimen was repeated weekly. Doses of 5-FU were escalated in cohorts of four or more patients from 2,000 to 2,600 mg/m2. Among 20 patients entered, the majority had colorectal cancer, and most had received prior 5-FU treatment. Toxicity was predominantly gastrointestinal, and diarrhea was dose-limiting at a 5-FU dose of 2600 mg/m2. There were three partial remissions observed, two of whom had colorectal cancer. Emerging data that casts doubt on the modulation value of PALA at this dose and schedule suggests that revision of this regimen be considered before Phase II trial.
Topics: Adult; Aged; Antimetabolites, Antineoplastic; Aspartic Acid; Colorectal Neoplasms; Drug Interactions; Female; Fluorouracil; Humans; Leucovorin; Male; Methylthioinosine; Middle Aged; Phosphonoacetic Acid
PubMed: 9220293
DOI: 10.1023/a:1005812923473 -
Cancer Investigation 1997The combination of N-(phosphonacetyl)-L-aspartate (PALA), 6-methylmercaptopurine riboside (MMPR), and 6-aminonicotinamide (6AN) has been shown to be an effective...
The combination of N-(phosphonacetyl)-L-aspartate (PALA), 6-methylmercaptopurine riboside (MMPR), and 6-aminonicotinamide (6AN) has been shown to be an effective antineoplastic regimen and also to enhance the effects of other antineoplastic agents (1-4). To further enhance the effect of this combination, we investigated the effects of adding adriamycin, at its maximally tolerated dose, to this regimen. The response rate (complete regression+partial regression) for the four-drug regimen was higher than for the three-drug regimen, and the tumor growth delay was also significantly higher than for treatment with PALA, MMPR, 6AN, or after treatment with maximally tolerated doses of adriamycin alone (11 mg/kg). The addition of adriamycin to PALA, MMPR, 6AN did not result in enhancement of the effect of radiation, as measured by tumor growth delay studies and tumor control (complete and partial regression rate). The mechanism of action of the combination of PALA, MMPR, and 6AN is not known definitively, but a possible mechanism previously suggested is biochemical modulation of energy metabolism and inhibition of production of tumor ATP. Treatment with PALA, MMPR, 6AN, and adriamycin (at 2.5 hr post MMPR, 6AN) resulted in a nadir NTP/Pi value, as determined by 31P NMR spectroscopy, at approximately 10 hr post MMPR + 6AN (7.5 hr post adriamycin), which was not significantly different from the NTP/Pi value determined after treatment with the three-drug combination.
Topics: 6-Aminonicotinamide; Animals; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Cell Division; Disease Progression; Doxorubicin; Drug Synergism; Evaluation Studies as Topic; Magnetic Resonance Spectroscopy; Mammary Neoplasms, Experimental; Methylthioinosine; Mice; Phosphorus Isotopes; Radiation-Sensitizing Agents
PubMed: 9095206
DOI: 10.3109/07357909709115763 -
Anti-cancer Drugs Aug 1996Paclitaxel alone is active against the CD8F1 murine spontaneous mammary cancer, and when administered following an ATP-depleting combination of... (Comparative Study)
Comparative Study
Paclitaxel alone is active against the CD8F1 murine spontaneous mammary cancer, and when administered following an ATP-depleting combination of N-(phosphonacetyl)-L-aspartate (PALA) + 6-methylmercaptopurine riboside (MMPR) + 6-aminonicotinamide (6-AN) (PMA) produced significantly enhanced partial tumor regressions over that produced by either paclitaxel alone at the maximal tolerated dose (MTD), or by the PMA drug combination alone, against advanced, first passage spontaneous murine breast tumors. The anticancer activity of paclitaxel is due to enhancement and stabilization of microtubule polymerization. Pertinently, microtubule disassembly (an ATP-dependent process) is known to sharply decrease in the presence of ATP depletion. Thus, the dramatic therapeutic enhancement observed with paclitaxel in combination with PMA is in agreement with biochemical expectations, since PMA has been shown to deplete ATP in CD8F1 tumor cells. The augmented therapeutic results were obtained with approximately one-third the MTD of paclitaxel as a single agent and suggest the potential clinical benefit of more effective treatment with lesser amounts of drug.
Topics: 6-Aminonicotinamide; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Female; Mammary Neoplasms, Experimental; Methylthioinosine; Mice; Paclitaxel; Phosphonoacetic Acid; Remission Induction
PubMed: 8913434
DOI: 10.1097/00001813-199608000-00006 -
Biochemical Pharmacology May 19966-mercaptopurine (6MP) cytotoxicity is caused by thioguanine and methylthioinosine nucleotides. Thiopurine methylation occurs to a large extent in vivo and in vitro. In...
6-mercaptopurine (6MP) cytotoxicity is caused by thioguanine and methylthioinosine nucleotides. Thiopurine methylation occurs to a large extent in vivo and in vitro. In this reaction, S-adenosyl-L-methionine (AdoMet), produced from methionine and ATP, is converted into S-adenosyl-L-homocysteine (AdoHcy) which, in turn, is hydrolyzed into homocysteine. Remethylation of homocysteine into methionine is inhibited by methotrexate (MTX). In cultured lymphoblasts, AdoMet: AdoHcy ratio and DNA methylation decrease after incubation with 6MP. The aim of the present study was to investigate the influence of high-dose 6MP on the methylation capacity in children with acute lymphoblastic leukemia. Five patients received 4 courses with high-dose intravenous MTX (5' g.m-2 in 24 hr) immediately followed by high-dose 6MP (1300 mg.m-2 in 24 hr). Five control patients received high-dose MTX and oral 6MP (25 mg.m -2 daily for 8 weeks). Leucovorin rescue was started at 36 hr in both groups. In the intravenous 6MP group, 6-methylmercaptopurine, its riboside, and 6-methylmercapto-8-hydroxypurine were detectable in plasma in concentrations of 0.3-2.6 muM (6MP steady state levels: 11.6 muM). In red blood cells, mean methylthioinosine nucleotide levels were one third of those of ATP (13.1 nmol/10(8)). AdoHcy levels (10 pmol/10(8)) remained constant in both groups and AdoMet was not detectable ( < 20 pmol/10(8)). In both groups, plasma homocysteine increased and methionine decreased following administration of MTX. The delay in the recovery of methionine in the intravenous 6MP group after MTX infusion is probably the result of an increased demand on methyl groups during 6MP infusion.
Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Erythrocytes; Homocysteine; Humans; Mercaptopurine; Methionine; Methotrexate; Methylation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purine Nucleotides; S-Adenosylhomocysteine; S-Adenosylmethionine
PubMed: 8645339
DOI: 10.1016/0006-2952(96)00032-9 -
In vivo detection by 31P NMR of pentose phosphate pathway block secondary to biochemical modulation.NMR in Biomedicine May 1996The chemotherapeutic regimen of N-(phosphonacetyl)-L-aspartate (PALA) followed 17 h later by 6-methylmercaptopurine riboside (MMPR) and 6-aminonicotanamide (6AN) has... (Comparative Study)
Comparative Study
The chemotherapeutic regimen of N-(phosphonacetyl)-L-aspartate (PALA) followed 17 h later by 6-methylmercaptopurine riboside (MMPR) and 6-aminonicotanamide (6AN) has been shown to be a potent sensitizer of anti-neoplastic therapy. We undertook this study to compare the therapeutic and metabolic effects of this triple drug combination vs one of its components, 6AN, in a murine mammary carcinoma. After treatment with PALA, MMPR and 6AN, a new peak was detected which was assigned to 6-phosphogluconate (6PG), which is a marker of inhibition of the pentose phosphate pathway at the 6-phosphogluconate dehydrogenase step. Treatment with PALA, MMPR and 6AN also induced a decrease in the ratios of nucleoside triphosphate/inorganic phosphate (NTP/Pi) and phosphocreatine/inorganic phosphate (PCr/Pi) similar to previous results with a different tumor model. These effects were most pronounced at 6 and 10 h. In addition, an increase in PME'/phosphocholine (PME' = downfield peak in the phosphomonoester region) was detected, which was expected because of the cytotoxic effect of this regimen. Treatment with 6AN alone also resulted in the detection of 6PG with a maximum intensity at 6 h post-6AN. Treatment with 6AN alone induced a smaller change in PME'/PC and failed to cause a decrease in PCr/Pi or NTP/Pi at 6 and 10 h. The enhanced response to the combination of PALA, MMPR and 6AN vs 6AN alone, both with regard to cytotoxicity and radiosensitization, may be due to energy depletion.
Topics: 6-Aminonicotinamide; Animals; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Cell Division; Magnetic Resonance Spectroscopy; Male; Mammary Neoplasms, Experimental; Methylthioinosine; Mice; Mice, Inbred C3H; Pentose Phosphate Pathway; Phosphonoacetic Acid; Phosphorus; Teratogens
PubMed: 8892397
DOI: 10.1002/(SICI)1099-1492(199605)9:3<114::AID-NBM413>3.0.CO;2-O -
Journal of Pediatric Hematology/oncology May 1996We investigated the metabolism of high dose 6 mercaptopurine (HD-6MP) infusions and its influence on the metabolism by allopurinol, an inhibitor of xanthine oxidase, the... (Clinical Trial)
Clinical Trial
PURPOSE
We investigated the metabolism of high dose 6 mercaptopurine (HD-6MP) infusions and its influence on the metabolism by allopurinol, an inhibitor of xanthine oxidase, the enzyme that catabolizes 6MP into thioxanthine and thiouric acid.
PATIENTS AND METHODS
Nine patients (aged 2-11 years) with non-Hodgkin lymphoma (NHL) were treated with HD-6MP (1300 mg/m(2).24h) within a therapeutic window after diagnosis. Four patients received oral allopurinol (200 mg/m(2).day) to prevent urate nephropathy, and five did not. Plasma and RBC were isolated before and 4, 20, 24, 28, and 48h after the start of the infusion. All measurements were performed with HPLC.
RESULTS
Considerable variations were found in the plasma levels of 6MP, thioxanthine, and thiouric acid and of RBC-MeTIN levels. 6MP-riboside was not detectable, and MeMP and MeMPR levels were <1.3 muM in the plasma. In general, 6MP, thioxanthine, and MeMP levels in plasma were higher, and thiouric acid plasma levels and RBC-MeTIN levels were lower in the patients treated with allopurinol compared to those who did not receive allopurinol.
CONCLUSIONS
6MP is extensively metabolized in patients with NHL treated with HD-6MP. Thiopurine methylation, at the levels of nucleotide, nucleoside, and base, is an important metabolic pathway after HD-6MP. Co-administration of allopurinol can result in both a decreased catabolism and anabolism of 6MP compared to treatment with HD-6MP alone. This observation may have consequences for the therapeutic efficacy and toxic effects of 6MP in combination with allopurinol.
Topics: Allopurinol; Antimetabolites, Antineoplastic; Antineoplastic Agents; Child; Child, Preschool; Dose-Response Relationship, Drug; Enzyme Inhibitors; Erythrocytes; Female; Humans; Hypoxanthine; Hypoxanthines; Individuality; Infusions, Intravenous; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Methylthioinosine; Nucleotides; Xanthine; Xanthine Oxidase; Xanthines
PubMed: 8846126
DOI: 10.1097/00043426-199605000-00009