Potentiation of the anti-tumor activity of 5FU by thymidine and its correlation with the formation of (5FU)RNA.
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Biomedical subjects
Publications and source records attributed to D Martin.
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The experiments described here illustrate the use of metabolic modulation to improve the therapeutic effectiveness of 5-fluorouracil (5FUra) in two murine tumor systems (CD8F1 mannary carcinoma and CD2F1 colon tumor 26). The manipulations chosen were based on the assumption that a major fraction of the anti-tumor activity of 5FUra is due to its incorporation into RNA and that the resulting 5FUra-RNA creates difficulty for a variety of cellular mechanisms requiring RNA processing and function. This hypothesis leads to the prediction that thymidine would promote the anti-neoplastic effect of 5FUra due to the following possible interactions: (i) sparing 5FUra from catabolic degradation by saturating the relevant enzymes wit thymidine; (ii) selective arrest of normal cells due to feedback inhibition of robonucleotide reductase by the accumulating thymidine triphosphate (TTP); and (iii) the high levels of TTP would also be expected to repress the anabolic conversion of 5FUra to the deoxy derivatives, thus preserving it for entry into RNA. The data show that thymidine (and certain other nucleosides) does in fact markedly stimulate the incorporation of 5FUra into nuclear RNA and that this event is paralleled by a striking icrease in anti-tumor activity. Kinetic analysis reveals that, although the injection of 5FUra leads to an immediate cessation of thymidylate synthetase activity, DNA synthesis continues at a lower rate for 12 hr and then ceases completely. At this point, in contrast to the earlier partial inhibition, the addition of thymidine fails to restore the ability of the tumor cells to synthesize DNA.
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A case of recurrent salivary gland enlargement occurring during fibreoptic oesophagoscopy and oesophageal stricture dilatation with Eder-Puestow dilators is described. The genesis of this condition is discussed and its transient and usually benign nature emphasized.
The influence of diurnal rhythms on several immune parameters was studied. When thymic-derived lymphocytes were collected 4 times during a 24-hour period, a variation occurred in the migration ability of these cells. The migration of T cells at 2:00 a.m. was markedly lower than at other time periods. Similar results were noted employing other T-cell tests: phytohemagglutinin wattle responsiveness and the graft vs. host assay.
To study once-daily antimicrobial prophylaxis of urinary tract infections, we gave trimethoprim-sulfamethoxazole (40 mg/200 mg), trimethoprim (100 mg), nitrofurantoin macrocrystals (100 mg), or placebo to 60 women for 6 months. During prophylaxis, infections per patient year were comparable in the groups receiving trimethoprim (0.0), nitrofurantoin (0.14), or trimethoprim-sulfamethoxazole (0.15) and occurred less frequently than in patients receiving placebo (2.8; P less than 0.001, placebo versus each drug regimen). The effectiveness of prophylaxis was limited to the 6 months that antimicrobials were given, and infections were more likely to develop after prophylaxis in women who had three or more infections in the year before prophylaxis (P less than 0.005). Further, women whose preprophylaxis infection was positive for antibody-coated bacteria were more likely to have same-strain relapse when infections recurred (P = 0.001). Emergence of trimethoprim-resistant Escherichia coli was rare, but non-E. coli infections occurred more often after prophylaxis (P less than 0.05). Prophylaxis with these drugs is effective, well tolerated, and did not produce emergence of resistant E. coli but may predispose to non-E. coli urinary tract infections after its discontinuation.
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Micropuncture techniques were employed to evaluate the effects of unilateral ureteral obstruction (UUO) of 18 h duration on the function of the terminal collecting duct in weanling rats 90-120 min following release of obstruction. In control animals and after release of UUO, water and sodium reabsorption continued along the terminal segment of the collecting duct. Fractional delivery of water (FRH2O) and sodium (FRNa) to this segment was increased after release of UUO. A significantly greater amount of the FRH2O and FRNa was reabsorbed along the terminal collecting duct following release of obstruction than in controls. Potassium was not consistently reabsorbed or secreted in either group. Following release of UUO, the osmolality of collecting duct fluid was lower than in controls, but was not different from the osmolality of fluid obtained from the bend of the loop of Henle. The results suggest that the permeability to water and the reabsorptive capacity of the collecting duct are not altered by acute obstruction.
Juxtamedullary (JM) nephron and collecting duct function was studied after a two-thirds reduction in renal mass in the young rat. The glomerular filtration rate of JM nephrons was twofold greater in the remnant kidney (RK) group than in controls, but this increase was proportional to the increase measured in surface nephrons. Despite an increase in absolute reabsorption, delivery of sodium and water to the end of the proximal tubule of superficial nephrons and to the bend of Henle's loop of JM nephrons was increased. This was a consequence of an increase in filtered load and a decrease in fractional reabsorption. Potassium handling in surface nephrons was similar to that of sodium and water. In deep nephrons of the RK group, potassium delivery to the bend was increased as a consequence of increased filtered load. The terminal portion of the collecting duct has a role in this adaptive response to a reduction in renal mass. In rats with a RK, reabsorption of water occurred along this segment; however, when the amount reabsorbed was related to delivery, fractional water reabsorption was only 30% of controls. Changes in sodium handling were more profound. In the group with the RK, sodium reabsorption was not detectable along this segment. Thus, while 40% of delivered sodium was reabsorbed in controls, in the remnant kidney group the mean was not different from zero (-1.7%).