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D S Martin

Publications and source records attributed to D S Martin.

At least 19 recordsLinked to original sources
PubMed1997

Evaluation of chemotherapy and radiation enhancement and 31P NMR spectral changes induced by biochemical modulation.

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.

6-Aminonicotinamide↗
PubMed1997

Phylogenetic relationships among eight Eimeria species infecting domestic fowl inferred using complete small subunit ribosomal DNA sequences.

Complete 18S ribosomal RNA gene sequences were determined for 8 Eimeria species of chickens and for Eimeria bovis of cattle. Sequences were aligned with each other and with sequences from 2 Sarcocystis spp., Toxoplasma gondii, Neospora caninum, and 4 Cryptosporidium spp. Aligned sequences were analyzed by maximum parsimony to infer evolutionary relationships among the avian Eimeria species. Eimecia bovis was found to be the sister taxon to the 8 Eimeria species infecting chickens. Within the avian Eimeria species, E. necatrix and E. tenella were sister taxa: this clade attached basally to the other chicken coccidia. The remaining Eimeria spp. formed 3 clades that correlated with similarities based on oocyst size and shape. Eimeria mitis and Eimeria mivati (small, near spherical oocysts) formed the next most basal clade followed by a clade comprising Eimeria praecox. Eimeria maxima, and Eimeria brumetti (large, oval oocysts), which was the sister group to Eimeria acervulina (small, oval oocysts). The 4 clades of avian Eimeria species were strongly supported in a bootstrap analysis. Basal rooting of E. necatrix and E. tenella between E. bovis and the remaining Eimeria species and the apparent absence of coccidia that infect the ceca of jungle fowl all suggest that E. necatrix and E. tenella may have arisen from a host switch, perhaps from the North American turkey, Meleagris gallopavo.

Animals↗
PubMed1997

Chemotherapeutically induced DNA damage, ATP depletion, and the apoptotic biochemical cascade.

The biochemical death cascade of apoptosis is separate from, although induced by, the anticancer drug-target interaction. The failure of many of our chemotherapeutic agents reflects an inability of anticancer drugs to induce apoptosis. Understanding the basic cellular mechanisms that control apoptosis will greatly increase our ability to treat cancer. Identification of the components of the apoptotic biochemical cascade will present new targets for complementary enhancement of chemotherapeutically induced cancer cell death. One factor that has been directly implicated in apoptosis is adenosine triphosphate (ATP). Nevertheless, in this regard, ATP is controversial. This commentary takes issue with dogma, and points to the need for additional thought and research in this field. ATP-depleting therapy of tumor-bearing mice has been shown to induce a marked therapeutic result with minimal mortality, and this effect can be further enhanced when combined with chemotherapy. The definitive mechanism of action is still controversial, although several mechanisms for ATP depletion have been implicated in the process. These include reduction in the mitochondrial transmembrane potential, activation of poly (ADP-ribose) polymerase (PARP) and depletion of the coenzyme nicotinamide adenine dinucleotide (NAD+). Even though the definitive experiments have yet to be carried out, the identification of ATP depletion as a critical determinant in apoptosis should allow for the development of new therapeutic strategies in the treatment of human cancer.

6-Aminonicotinamide↗
PubMed1996

A phase I trial of a modified, dose intensive FAMTX regimen (high dose 5-fluorouracil+doxorubicin+high dose methotrexate+leucovorin) with oral uridine rescue.

BACKGROUND: Dose intensification of 5-fluorouracil (5-FU) is complicated by increased toxicity. 5-FU is a fluorine-substituted pyrimidine analog of uracil. In preclinical studies, administration of oral uridine (Ur) has been shown to allow for dose intensification of 5-FU with enhancement of its antitumor activity. Therefore, a Phase I trial was designed aimed at dose intensification of 5-FU as a component of a modified 5-FU-doxorubicin-methotrexate (FAMTX) regimen using oral Ur rescue. METHODS: Methotrexate (MTX) was administered to all patients at a fixed dose of 1.5 g/m2. MTX was followed 24 hours later by escalating doses of 5-FU starting at 800 mg/m2 with leucovorin rescue. Cycles of 5-FU and MTX were repeated every 15 days. Every other cycle, patients received doxorubicin. "Adria cycles") at a dose of 30 mg/m2. Oral Ur was administered at a dose of 8 gm/m2 every 6 hours for 12 doses. In the first phase of the study, patients received Ur only if they developed Grade 3 or 4 hematologic toxicity. In the second phase, all patients received Ur 24 hours after 5-FU on all cycles. RESULTS: Without Ur rescue, the maximum tolerated dose (MTD) of 5-FU was 900 mg/m2 on the Adria cycles and 1.1 gm/m2 on the non-Adria cycles. With Ur, the MTD of 5-FU increased to 1.2 gm/m2 on the Adria cycles and to 1.6 gm/m2 on the non-Adria cycles. CONCLUSIONS: In this modified FAMTX regimen, oral Ur administration allowed for dose-intensification of 5-FU, with a 33% increase in the MTD of 5-FU on the Adria cycles and a 45% increase in the MTD of 5-FU dose on the non-Adria cycles.

Administration, Oral↗
PubMed1996

Apolipoprotein E polymorphism does not predict risk of restenosis after coronary angioplasty.

A recent report has suggested that the E4 allele of apolipoprotein (apo) E increases the risk of restenosis after percutaneous transluminal coronary angioplasty (PTCA) and also that it interacts synergistically with the deletion (D) allele of the angiotensin-converting enzyme (ACE) to increase the risk sixteen-fold. To investigate this further, we genotyped 231 subjects with successful PTCA who underwent planned repeat angiography at 4 months to assess the degree of restenosis. Subjects carrying the apo E4 allele (n = 71) were well matched with non-carriers (n = 160) for clinical and pre- and post-PTCA angiographic features. We found no increase in either apo E4 allele frequency (18.4% versus 15.6%, P = 0.42) or apo E4 homozygosity (2/106 versus 5/125, P = 0.30) in those with restenosis compared with those without. The relative risk of restenosis for apo E4 carriers was 1.11 (95% CI = 0.87-1.42). In apo E4 carriers, restenosis frequency was similar in those also carrying the ACE D allele and those without (28/55 (50.9%) versus 9/16 (56.2%), P = 0.71) and there was no significant increase in restenosis risk in carriers of both the apo E4 and ACE D alleles compared to the rest (odds ratio 1.30, 95% CI 0.68-2.50, P = 0.39). We conclude that in our cohort, the apo E4 allele does not either independently or acting synergistically with the ACE D allele increase the risk of restenosis after PTCA, and that apo E genotyping will not be a useful predictor of risk before the procedure.

Alleles↗
PubMed1996

Correlation of retention of tumor methylmercaptopurine riboside-5'-phosphate with effectiveness in CD8F1 murine mammary tumor regression.

Treatment with a combination (PMA) of (N-phosphonacetyl)-L-aspartic acid (PALA), methylmercaptopurine riboside (MMPR), and 6-aminonicotinamide (6AN) induced partial regressions of CD8F1 murine mammary tumors and provided for tumor growth inhibition without regression of Colon 38 tumors. HPLC-nucleotide pool analysis of CD8 mammary tumors obtained at various times after treatment with PMA revealed that MMPR-5'-phosphate, which inhibits de novo purine nucleotide biosynthesis, was constant at levels of approximately 2.5 nmol/mg protein for 72 hr after treatment. In contrast, the MMPR-5'-phosphate levels of C38 tumors decreased from 24-hr levels at 1.5 nmol/mg protein with a half-time of about 24 hr. Treatment of CD8 tumor-bearing mice with iodotubercidin, a potent inhibitor of adenosine/MMPR kinase, at various times after PMA, reversed both the accumulation of high levels of MMPR-5'-phosphate and the number of partial tumor regressions. These data demonstrate that a cycle of MMPR rephosphorylation is active in the CD8 mammary tumor and suggest that this recycling of MMPR is important for the optimal effect of PMA treatment.

6-Aminonicotinamide↗
PubMed1996

In vivo detection by 31P NMR of pentose phosphate pathway block secondary to biochemical modulation.

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.

6-Aminonicotinamide↗
PubMed1996

Effect of 6-aminonicotinamide on the pentose phosphate pathway: 31P NMR and tumor growth delay studies.

6-aminonicotinamide (6AN) has been shown to enhance radiosensitivity in vitro, although previous in vivo studies failed to show an effect. 31P NMR spectra were obtained by using a one-dimensional chemical shift imaging technique on a first generation transplant of the CD8FI spontaneous mammary carcinoma tumor model. Spectra were obtained both before and 10 h after treatment with 6AN (20 mg/kg). Changes in pH, nucleoside triphosphate/inorganic phosphate, and phosphocreatine/ inorganic phosphate measured at 10 h post-6AN were not significant. A new peak was detected 10 h post-6AN, which was assigned to 6-phosphogluconate (6PG), indicating inhibition of the pentose phosphate pathway (PPP). Based on the spectral data demonstrating inhibition of the PPP at 10 h post-6AN, tumor-bearing mice were irradiated (15 Gy x 3 fractions) on Days 1, 10 or 11, and 21 10 h after administration of 6-aminonicotinamide (20 mg/kg). Tumor-bearing mice receiving 6AN alone (20 mg/kg x 3), radiation alone (15 Gy x 3), or saline were also studied. Tumor growth delay studies indicated that 6AN alone induced a small but significant tumor growth delay (4.3 +/- 0.8 days). Radiation alone induced a tumor growth delay of 34.5 +/- 2.7 days. Treatment with 6AN followed by radiation induced a tumor growth delay of 57.0 +/- 3.8 days. This was significantly greater than the TGD values for treatment with 6AN alone or radiation (P < 0.01). No complete regressions were noted after treatment with 6AN or radiation alone. Concomitant therapy with 6AN plus radiation yielded 6/28 complete regressions (21%), which was significantly greater than radiation (P < 0.05) or 6AN alone (P < 0.01) on this mammary carcinoma.

6-Aminonicotinamide↗
PubMed1996

Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine ribonucleoside.

Inhibition of pyrimidine and purine synthesis has been demonstrated to potentiate 5-fluorouracil (5-FU) activity in preclinical models. Low-dose phosphonacetyl-L-aspartate (PALA) potentiates the incorporation of 5-FU into RNA, without detectably increasing its toxicity. 6-Methylmercaptopurine riboside (MMPR) results in inhibition of purine biosynthesis with elevation of phosphoribosyl pyrophosphate (PRPP), which in turn is believed to increase the phosphorylation and intracellular retention of 5-FU. We conducted a phase I clinical trial to determine the maximum tolerated dose of 5-FU in combination with low-dose PALA and a biochemically-optimized dose of MMPR. The regimen consisted of PALA 250 mg/m2 given on day 1, followed 24 h later by MMPR 150 mg/m2, and escalating doses of 5-FU from 1625 to 2600 mg/m2 by 24 h continuous infusion. This regimen was repeated weekly. A group of 29 patients with a diagnosis of malignant solid tumor were entered; their median performance status was 1. The dose-limiting toxicity was mucositis, while other gastrointestinal toxicity was minimal. Two patients also experienced ischemic chest pain during the 5-FU infusion. The maximum tolerated dose of 5-FU in this combination was 2600 mg/m2. Several responses were observed including a complete remission in a previously treated breast cancer patient and two partial responses in breast and colon cancer. MMPR pharmacokinetics were obtained from urine analyses in 21 patients on this trial; there was no correlation between the pharmacokinetics of MMPR and the toxicity observed. This regimen was well tolerated and phase II trials are warranted using PALA 250 mg/m2, MMPR 150 mg/m2, and 5-FU 2300 mg/m2 by continuous infusion over 24 h.

Adult↗
PubMed1996

Enhanced antitumor activity of an adriamycin + 5-fluorouracil combination when preceded by biochemical modulation.

A three-drug combination, PMA, consisting of (phosphonacetyl)-L-aspartic acid + 6-methylmercaptopurine riboside + 5-aminonicotinamide, preceding either 5-fluorouracil (5-FU) or adriamycin (Adr), produced tumor-regressing activity in a murine advanced breast tumor model not attainable with either 5-FU or Adr as single agents, or with any lesser combination of these drugs administered at maximally tolerated doses. Marked tumor-regressing activity was further increased significantly by using 5-FU and Adr together in conjunction with the modulatory biochemical conditioning (particularly ATP depletion) provided by pretreatment with PMA.

Animals↗
PubMed1996

Marked enhancement in vivo of paclitaxel's (taxol's) tumor-regressing activity by ATP-depleting modulation.

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.

6-Aminonicotinamide↗
PubMed1996

The Coventry Award. Polymerase chain reaction detection of bacterial infection in total knee arthroplasty.

Synovial fluid aspirates from 50 patients with symptoms after total knee arthroplasty were analyzed by means of the polymerase chain reaction for the presence of bacterial deoxyribonucleic acid indicative of infection. Synovial fluid specimens were processed using a rapid bacterial lysis and extraction protocol, subjected to polymerase chain reaction amplification using universal bacterial primers, and polymerase chain reaction products analyzed by deoxyribonucleic acid hybridization methodology. Polymerase chain reaction testing on preoperative aspirates yielded 32 specimens positive for bacterial infection. Standard microbiologic culturing assays performed on the same samples gave 6 positive bacterial infection tests; intraoperative culturing identified 9 additional infected specimens. All culture positive specimens were polymerase chain reaction positive; in contrast, there were no false polymerase chain reaction positives in 21 negative control specimens obtained from aseptic joints. The synovial fluid processing protocol and polymerase chain reaction analysis can be performed with a minimum of time and may provide greater sensitivity than standard diagnostic tests. In view of the high incidence of false negative test results from standard microbiologic assays of synovial fluid specimens, the use of molecular biology based bacterial detection methodology should provide an additional, or alternative, assay to identify infected patient specimens.

Awards and Prizes↗
PubMed1996

Acute stress increases venomotor tone in conscious rats.

This study tested the hypothesis that acute psychological stress causes venoconstriction. Male Sprague-Dawley rats were instrumented with indwelling catheters in a femoral artery and vein and a balloon-tipped catheter in the right atrium. Mean arterial pressure (MAP), venous pressure, heart rate (HR), and mean circulatory filling pressure (MCFP) were monitored in conscious rats. Air-jet stress was performed before and after treatment with saline, chlorisondamine, phentolamine, or prazosin. Air-jet stress caused MAP, HR, and MCFP to increase by 10 +/- 1 mmHg, 31 +/- 4 beats/min, and 0.95 +/- 0.09 mmHg, respectively. Treatment with either chlorisondamine or phentolamine was equally effective in abolishing the stress-induced increases in MAP, HR, and MCFP. Prazosin treatment abolished the pressor response to air-jet stress but did not significantly affect the HR and MCFP responses. In contrast, pretreatment with the alpha 2-receptor antagonist rauwolscine hydrochloride abolished both the MAP and MCFP responses to air-jet stress but did not affect the HR response. These findings indicate that venoconstriction is an important component of the cardiovascular response to acute psychological stress. Stress-induced venoconstriction appears to be mediated primarily via the alpha 2-receptor subtype.

Acute Disease↗
PubMed1995

Biochemical modulation of tumor cell energy. IV. Evidence for the contribution of adenosine triphosphate (ATP) depletion to chemotherapeutically-induced tumor regression.

DNA-damaging agents, e.g. Adriamycin (ADR), are reported to cause tumor regression by induction of apoptosis. A reduction in the intracellular content of ATP is part of the biochemical cascade of events that ultimately results in programmed death of the cell, or apoptosis. A chemotherapeutic three-drug combination (PMA) consisting of N-(phosphonacetyl)-L-aspartate (PALA) + 6-methylmercaptopurine riboside (MMPR) + 6-aminonicotinamide (6AN) significantly lowers levels of ATP in CD8F1 murine breast tumors in vivo and produces tumor regression by apoptosis. Addition of the DNA-damaging antitumor agent ADR to PMA was found to further significantly deplete ATP in CD8F1 murine breast tumors in vivo with a concomitant significant increase in the number of tumor regressions. The correlative biochemical and therapeutic results are consistent with, and support, the hypothesis that ATP depletion is a significant factor and, therefore, is a worthy therapeutic target in the production of apoptosis.

6-Aminonicotinamide↗