Thermopower and conductivity of InAs/GaSb crossed-gap heterostructures in a magnetic field.
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Journal Article↗
Biomedical subjects
S Cao
Publications and source records attributed to S Cao.
Role of fluoropyrimidine Schedule and (6R,S)leucovorin dose in a preclinical animal model of colorectal carcinoma.
BACKGROUND: Fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd), used alone or in combination with other cytotoxic agents, exhibit limited efficacy in the treatment of advanced gastrointestinal cancer. (6R,S)leucovorin (LV), a source of reduced folate cofactor, can modulate (i.e., enhance) the therapeutic efficacy of treatment with these fluoropyrimidines (FPs). The role of FP schedule and lv dose in modulating FP antitumor activity, using clinically relevant drug doses and schedules, has not been fully documented. PURPOSE: We evaluated the antitumor activities and the toxic effects of 5-FU and FdUrd, used either alone or in combination with LV, by following three clinically relevant treatment schedules in rats bearing advanced ward colorectal carcinomas. METHODS: Maximum tolerated doses (MTDs), i.e., doses producing a reversible body weight loss of no more than 20% with no lethality, of 5-FU and FdUrd, either individually or in combination with LV, were used in the following treatment schedules: (I) 4 days of continuous intravenous FP infusion (with or without a daily 2-hour lv infusion); (II) a daily FP intravenous push for 4 days (LV, when given, was administered as a 2-hour infusion, with the FP push given after the first hour of LV treatment); and (III) an FP intravenous push given weekly for 3 weeks (the coadministration of LV and FP was performed as in schedule II). In these studies, LV was given at either a low dose (20 mg/kg [body weight] per day) or a high dose (200 mg/kg per day). The MTDs of 5-FU and FdUrd, with or without LV, were defined in normal rats. Antitumor activities were assessed in animals 12-14 days after they received subcutaneous tumor implants. Toxic effects at the MTD were evaluated in both normal and tumorbearing animals. RESULTS: With schedules I and II, the MTD of 5-FU alone was 35 mg/kg per day; with schedule III, it was 100 mg/kg per week. For FdUrd alone, the MTD was 100 mg/kg per day with schedules I and II and 400 mg/kg per week with schedule III. Coadministration of LV reduced the MTD of both 5-FU and FdUrd by approximately 25%-30%, irrespective of the LV dose used. The dose-limiting toxic effects of treatment with 5-FU and FdUrd were diarrhea and/or stomatitis, the relative severity of which depended on the schedule of FP administration. The profile of toxic effects was not altered by LV when used at either dose. FP antitumor activity was modulated by LV in all three treatment schedules, but the greatest effects were seen using schedule III, where more complete tumor regression was seen with high-dose LV than with low dose LV. LV potentiated the antitumor activity of FdUrd to a greater extent than that observed with 5-FU. CONCLUSIONS: In this rat model of colorectal carcinoma, the extent to which FP antitumor activity is modulated by LV depends on the schedule of FP administration and the dose of LV used.
Animals↗
Elevations in IFN-gamma, IL-5, and IL-10 in patients with the autoimmune disease primary biliary cirrhosis: association with autoantibodies and soluble CD30.
Antimitochondrial antibodies (AMA) which recognize the E2 component of the pyruvate dehydrogenase complex are found in virtually all patients with the autoimmune liver disease primary biliary cirrhosis (PBC). The factors that contribute to elevated AMA and the relationship of the autoantibodies to disease pathogenesis have not been elucidated. Since cytokines are important regulators of antibody production and isotype switching, the association of specific cytokines to antibody production was examined in patients with PBC. Elevations in IL-2, IFN-gamma, IL-4, IL-5, and IL-10 were detected in serum from patients with PBC. However, only IFN-gamma (6012 +/- 1128 pg/ml vs 147 +/- 89 pg/ml, P < 0.0001) and IL-5 (382 +/- 103 pg/ml vs 29 +/- 12 pg/ml, P < 0.001) were significantly elevated compared to normal controls. Moreover, there was a positive correlation in the levels of IFN-gamma, and to a lesser extent IL-5, with the levels of soluble CD30 (sCD30) in the circulation. The elevated levels of sCD30 detected in patients with PBC (194 +/- 29 U/ml vs 39 +/- 9 U/ml in normal controls) suggest that CD30+ cells may produce cytokines, which contribute to the immune abnormalities in patients with PBC.
Autoantibodies↗
[Reversion of malignant phenotypes of human lung squamous carcinoma cells by ornithine decarboxylase antisense RNA].
Abnormally elevated activity of ornithine decarboxylase (ODC), with subsequent polyamine accumulation are intimately associated with the genesis, development and metastasis of cancer. Therefore, ODC antisense RNA was used to transfect human lung squmous carcinoma cell line LTEP-78. Compared with the parental cells, growth of the antisense transfected LTEP-78 cells arrested in G0/G1 phase and colony formation in soft agar and tumorigenicity in nude mice were significantly reduced. Nucleic acid hybridization demonstrated the expression of ODC antisense RNA and the content of ODC mRNA was markedly reduced. The results suggest that the reversion of malignant phenotypes of human lung squamous carcinoma cells is associated with the control of polyamine biosynthesis.
Animals↗
[Advances in the research on new generation of oral contraceptive agents].
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Contraceptives, Oral, Synthetic↗
d,l-buthionine-(S,R)-sulfoximine potentiates in vivo the therapeutic efficacy of doxorubicin against multidrug resistance protein-expressing tumors.
Intracellular glutathione (GSH) has been implicated as a regulatory determinant of multidrug resistance protein (MRP) function. The objective of the present study was to evaluate in vivo the ability of d,l-buthionine-(S,R)-sulfoximine (d,l-BSO), a potent inhibitor of GSH biosynthesis, to reverse MRP-mediated drug resistance to doxorubicin. Athymic nude mice (nu/nu) bearing advanced parental human fibrosarcoma HT1080 and MRP-expressing HT1080/DR4 tumors were treated with the maximum tolerated dose of doxorubicin (10 mg/kg, i. v. push). This therapy produced an overall response rate of 50% (20% complete response and 30% partial response) in mice bearing parental HT1080 xenografts, whereas no significant antitumor activity against HT1080/DR4 tumors was observed. Treatment of mice bearing HT1080 and HT1080/DR4 xenografts with a continuous i.v. infusion of nontoxic doses of d,l-BSO (300 and 600 mg/kg/day) produced a 60% reduction of GSH plasma levels and greater than 95% reduction in GSH tumor levels in both parental and multidrug-resistant tumors; however, this treatment possessed no in vivo antitumor activity by itself. Under these treatment conditions, a combination of d,l-BSO with the maximum tolerated dose of doxorubicin administered at 24 h during a 48-h i.v. infusion of d,l-BSO completely restored the response of MRP-expressing HT1080/DR4 tumors to doxorubicin (overall response rate, 63%; complete response rate, 38%) with no potentiation of host toxicity. The d,l-BSO-induced in vivo reversal of MRP-mediated drug resistance correlated in vitro with the restoration of intracellular doxorubicin retention in cultured HT1080/DR4 cells. Depletion of GSH by d,l-BSO in drug-sensitive HT1080 tumors that do not express MRP did not alter the in vivo response to doxorubicin. Using the same treatment schedule, dose, and administration of doxorubicin with and without d,l-BSO in nude mice bearing P-170 glycoprotein-expressing A2780/Dx5 tumors, no potentiation of the therapeutic index of doxorubicin was found, demonstrating the in vivo selectivity of d, l-BSO-induced GSH depletion on MRP-function. The data reported herein indicate that in vivo function of MRP as a mediator of doxorubicin resistance requires the presence of sufficient GSH pools. d,l-BSO may provide an example of an effective in vivo modulator of MRP-mediated drug resistance.
Animals↗
PAK-104P, a pyridine analogue, reverses paclitaxel and doxorubicin resistance in cell lines and nude mice bearing xenografts that overexpress the multidrug resistance protein.
Multidrug resistance (MDR) is considered multifactorial and has been associated with overexpression of the multidrug resistance protein (MRP). However, effective compounds for reversal of MRP-related MDR are limited. In the present study, the modulatory activity of the novel pyridine analogue PAK-104P on MRP-mediated resistance to doxorubicin and paclitaxel was investigated in two doxorubicin-selected human tumor cell lines [HT1080/DR4 (sarcoma) and HL60/ADR (leukemia)] and compared with the nonimmunosuppressive cyclosporine analogue PSC-833. In cell lines HT1080/DR4 (MRP/lung resistance-related protein phenotype) and HL60/ADR (MRP phenotype), doxorubicin resistance was significantly higher (250-fold and 180-fold, respectively) than that to paclitaxel (6-fold and 9-fold, respectively). With noncytotoxic concentrations of PAK-104P (1 and 5 microM), the reversal of doxorubicin resistance was significant but partial in HT1080/DR4 and HL60/ADR cells (dose-modifying factor for 5.0 microM PAK-104P, 25.0 and 31.2, respectively), whereas complete reversal of paclitaxel resistance was achieved in HL60/ADR cells. In contrast, PSC-833 modulation of doxorubicin and paclitaxel resistance was modest. Cellular drug uptake and retention studies by flow cytometry analysis demonstrated that PAK-104P was effective in restoring cellular doxorubicin concentrations in resistant cells to levels comparable to those obtained in parental cells. In athymic nude mice, PAK-104P significantly potentiated the therapeutic efficacy of doxorubicin and paclitaxel against resistant HT1080/DR4 xenografts. Of significance is that the maximum tolerated doses of doxorubicin and paclitaxel were administered in combination with PAK-104P, documenting improvement in the therapeutic index of these agents. In addition to reversing P-glycoprotein-mediated MDR, the pyridine analogue PAK-104P provides an example of an effective in vivo modulator of MRP-mediated MDR.
ATP-Binding Cassette Transporters↗
Polyglutamylation of the dihydrofolate reductase inhibitor gamma-methylene-10-deazaaminopterin is not essential for antitumor activity.
As part of a continuing program aimed at developing nonpolyglutamylatable inhibitors of dihydrofolate reductase that are less toxic and more specific in their action, we herein report the therapeutic efficacy and toxicity of gamma-methylene-10-deazaaminopterin (MDAM) in athymic nude mice bearing advanced human HCT-8 ileocecal xenografts and its antitumor activity in C57BL/6 x DBA/2 F1 (hereafter called B6D2F1) mice bearing P388 murine leukemia. For the xenograft study, MDAM was administered at the maximum tolerated dose by the following dose schedules: (a) 5-day continuous i.v. infusion at 1.0 mg/kg/day (schedule I); and (b) i.v. push, daily for 5 days at 50 mg/kg/day (schedule II). The maximum tolerated dose values for methotrexate (MTX) under these conditions were 0.2 and 1.0 mg/kg/day for schedule I and schedule II, respectively. MTX did not exhibit any significant antitumor activity in this model system by both schedules; however, MDAM induced complete responses of 13 and 25% and partial responses of 25 and 50% by schedules I and II, respectively. MDAM also exhibited antitumor activity significantly superior to that of MTX in the P388 tumor model. One of the enantiomers of MDAM, which possesses the natural configuration at the gamma-methyleneglutamate moiety (l-MDAM), has been shown to be a better inhibitor of human recombinant dihydrofolate reductase and H35 hepatoma cell growth than D,L-MDAM. L-MDAM inhibited the uptake of radiolabeled folinic acid to H35 hepatoma cells eight times more efficiently than MTX. The results indicate that the superior activity of MDAM relative to MTX may be partially due to a combination of enhanced transport to tumor cells and slower deactivation by aldehyde oxidase.
Aminopterin↗
5-Ethynyluracil (776C85): effects on the antitumor activity and pharmacokinetics of tegafur, a prodrug of 5-fluorouracil.
We studied the effects of 5-ethynyluracil (776C85 and 776C), a potent mechanism-based inactivator of dihydropyrimidine dehydrogenase, on the antitumor efficacy and pharmacokinetics of tegafur (FT), a prodrug of 5-fluorouracil (5-FU), in rats with large s.c. colon carcinoma. Rats were dosed p.o. once daily for 7 days with either FT, FT and uracil in a 1:4 molar ratio (UFT), FT 1 h after 776C (776C/FT), or UFT 1 h after 776C (776C/UFT). 776C, which was dosed at 1 mg/kg, had neither intrinsic antitumor activity nor toxicity. The rank order in antitumor efficacy at the maximal tolerated dose of the FT (mg/kg/day) component was 776C/FT (5 mg/kg/day) > or = UFT (80 mg/kg/day) = 776C/UFT (5 mg/kg/day) >> FT (200 mg/kg/day). One-hundred % of rats treated with 776C/FT had complete and sustained tumor regression with no severe toxicity. The area under the plasma 5-FU concentration versus the time curve generated from UFT, FT, and 776C/FT at their maximum tolerated dose was 140, 50, and 27 microM.h, respectively. The area under the concentration in plasma versus time curve did not correlate with the rank order of antitumor efficacy. The vast majority of 5-FU derived from FT (alone) appeared to be rapidly catabolized. Furthermore, plasma exposure of 5-FU derived from UFT was more variable than that from 776C/FT. Each therapy also produced different levels of plasma uracil. Endogenous plasma uracil levels (1-3 microM) were not affected by FT but increased to 100 microM after dosing with 776C. Plasma uracil from UFT was 800 microM 1 h after dosing. These results suggest that moderately elevated uracil (776C/FT) may be beneficial, whereas uracil that is greatly elevated during the first 5 h (UFT) and 5-FU catabolites (FT alone) may interfere with antitumor efficacy. 776C, coadministered with FT, could provide once-a-day oral therapy for cancer patients.
Animals↗
Attenuation of the antitumor activity of 5-fluorouracil by (R)-5-fluoro-5,6-dihydrouracil.
5-Ethynyluracil (5-EU; 776C85) is a potent mechanism-based inactivator of dihydropyrimidine dehydrogenase that improves the antitumor activity of 5-fluorouracil (5-FU) to a greater extent than can be accounted for by the improved 5-FU pharmacokinetics that result from preventing the catabolism of 5-FU. We therefore tested the effects of (R)-5-fluoro-5,6-dihydrouracil (5-FUH2), the 5-FU catabolite extensively formed in the absence of 5-EU, on the antitumor activity and toxicity of 5-FU in 5-EU-treated rats bearing large s.c. tumors. Rats were dosed once weekly for 3 weeks with the following regimens: 100 mg/kg 5-FU (maximum tolerated dose), 10 mg/kg 5-FU 1 h after 1 mg/kg 5-EU, or 10 mg/kg 5-FU plus 90 mg/kg 5-FUH2 1 h after 1 mg/kg 5-EU. The latter regimen was designed to approximate the exposure produced from 5-FU in the absence of 5-EU, where > 80% of the dose is catabolized. 5-FU produced complete and sustained tumor regressions in 94% of the animals pretreated with 5-EU. In contrast, 5-FU in combination with 5-FUH2 produced complete regression in only 38% of the 5-EU-treated rats, which was similar to the antitumor activity of 5-FU in the absence of 5-EU. All treatments resulted in 7-11% transient weight loss. 5-FU produced no other notable toxicity in 5-EU-treated rats. However, 5-FUH2 added to this regimen caused transient diarrhea and stomatitis in 13% of the animals, which was similar to the toxicity produced by 5-FU in the absence of 5-EU. Thus, 5-FUH2, or other downstream catabolites of 5-FU, impaired the antitumor activity and slightly increased the toxicity of 5-FU. Accordingly, 5-EU approved to improve the efficacy of 5-FU by preventing the formation of 5-FU catabolites.
Animals↗
Modulation of the antitumour activity of cisplatin alone and in combination with 5-fluoro-2'-deoxyuridine by N-phosphonacetyl-L-aspartate in murine colon carcinoma no. 26.
Modulation of the therapeutic efficacy of cisplatin (CDDP) and 5-fluoro-2'-deoxyuridine (FdUrd) alone and in combination with N-phosphonacetyl-L-aspartate (PALA) was evaluated in mice bearing colon carcinoma (C-26) using a weekly intravenous (i.v.) push schedule for 3 weeks. A non-toxic dose of PALA (100 mg/kg) was administered i.v. 24 h prior to the i.v. administration of CDDP +/- FdUrd. The maximum tolerated doses (MTD) of CDDP and FdUrd when used as a single agent were 9 and 400 mg/kg, respectively. In combination, however, the MTD of CDDP and FdUrd were 2.5 and 300 mg/kg, respectively. PALA did not significantly affect the MTD. PALA improved the antitumour activity of CDDP or FdUrd when used alone; however, the highest tumour response, 66% complete tumour regression, was achieved with a PALA modulation of CDDP and FdUrd in combination.
Animals↗
[Clinical application of luteinizing hormone releasing hormone agonist and its impact on bone metabolism].
OBJECTIVES: To evaluate the efficacy of luteinizing hormone releasing hormone agonist (LHRH-A) in the treatment of endometriosis (Em), uterine leiomyoma and adenomyosis, and its impact on bone metabolism. METHODS: Twenty patients, Em 13 (stage II4, III7, IV2), leiomyoma 4 and adenomyosis 3, were selected to receive LHRH-A 200 micrograms intramuscular daily for 3 months. Clinical and ultrasound features serum follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), osteocalcin (BGP) concentrations were compared before and at the end of treatment. Furthermore, 24-hour urinary calcium (Ca), phosphate (P) excretions and bone mineral density (BMD) of radius and lumbar spine measured by single photon absorptiometry (SPA) and dual energy X-ray absorptiometry (DEXA) were also analysed before and at the end of treatment. Patients were followed-up 3-19 months after discontinuation of the drug. RESULTS: At the end of treatment dysmenorrhea disappeared in all 15 cases. Pelvic tenderness and induration improved in 18, endometrioma shrinked in 13 cases. Mean uterine volume of 7 patients with leiomyoma or adenomyosis was reduced by 35% from the basal volume. Serum LH, E2 levels were suppressed significantly (P < 0.05), mean E2 concentration declined from 459.5 +/- 292.0 to 160.3 +/- 110.7 pmol/L (P < 0.001). No significant change was found in serum BGP, urinary Ca, P, and BMD of radius and lumbar spine at the end of therapy, The only side effect was mild not flushes and sweating during treatment. After stopping the drug, 17 patients resumed menses within 2 months. Dysmenorrhea and pelvic mass recurred in 6 months with less severity. One became pregnant in 3 months. CONCLUSIONS: LHRH-A administration is effective in the treatment of Em, leiomyoma and adenomyosis. No significant adverse effect was shown on bone metabolism at the end of 3-month therapy.
Adult↗
Electric acupuncture treatment of peripheral nerve injury.
54 cases of peripheral nerve injury were treated by electric acupuncture and compared with 54 control cases treated with supportive medication. The changes after treatment were observed chiefly by electromyography while sensory and motor improvement were also recorded as auxiliary indicators. The therapeutic results in the acupuncture group were 5 cases cured, 26 markedly effective, 19 improved, and 4 cases failed, a total effective rate of 92.6% in contrast to the 55.6% for the controls. Analysis of the therapeutic results showed that 1) those in the acupuncture group were significantly better than in the control group; 2) nerve injuries should be treated as early as possible; 3) the radial nerve and the common peroneal nerve recovered faster than others; 4) cases not surgically explored recovered faster than those that were, and 5) patients with prompt propagation of the needling sensation recovered significantly faster than those with slow propagation.
Acupuncture Therapy↗
5-Fluorouracil prodrug: role of anabolic and catabolic pathway modulation in therapy of colorectal cancer.
Following p.o. administration to rats bearing advanced colorectal carcinoma, Ftorafur (FT) is converted to 5-fluorouracil (FUra) by microsomal P450 in the liver. To optimize the therapeutic selectivity of the FUra generated from FT, three approaches were utilized: (a) inhibition of FUra degradation to dihydrofluorouracil by uracil as an alternative substrate for uracil reductase in the molar ratio of 4 uracil:1 FT (UFT); (b) modulation of drug inhibition of thymidylate synthase by leucovorin (LV); and (c) by increasing the level of FUra incorporation into cellular RNA by N-(phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartate transcarbomylase. The maximum tolerated dose (MTD) of FT and UFT, administered 3 times a day for 28 days, was 150 mg/kg/day and 60 mg/kg/day, respectively. The MTDs were not significantly modified by LV (150 or 600 mg/kg/day), administered by the p.o. route with the drugs, or by PALA (100 mg/kg) administered weekly by the i.v. route. The dose-limiting toxicity of FT alone and in combination with the modulators was stomatitis. The severe alopecia observed with FT alone was reduced significantly by uracil. At the MTD, the antitumor activity of UFT was superior to those of FT and FUra alone and in combination with LV and/or PALA. The 3-month sustained complete tumor regression for UFT, FT, and FUra was 38%, 0%, and 13% (for the weekly schedule), respectively. Although uracil, LV, and PALA individually increased the antitumor activity of FT at its MTD, the combination of the three modulators produced the highest therapeutic efficacy in rats bearing advanced colorectal carcinoma, in which 100% of the treated animals achieved complete and sustained tumor regression. The therapeutic efficacy observed with FT modulation could not be achieved with FUra administered by different schedules, each at its MTD alone or in combination with either LV or PALA. In brief, modulation of FT produced greater therapeutic efficacy and selectivity than FUra. Furthermore, the combined use of modulators capable of inhibiting the degradation pathway of FUra and potentiating the effects of the anabolic metabolites action appears to offer the greatest therapeutic potential.
Animals↗
5-Ethynyluracil (776C85): modulation of 5-fluorouracil efficacy and therapeutic index in rats bearing advanced colorectal carcinoma.
5-Ethynyluracil (EU; 776C85) is a potent inactivator of dihydropyrimidine dehydrogenase, the enzyme that rapidly degrades 5-fluorouracil (FUra). We have investigated the antitumor activity and toxicity of FUra alone and in combination with EU in rats bearing advanced colon carcinoma. Two schedules were studied: (a) FUra daily for 4 days i.v. push (daily x 4); and (b) FUra administered i.v. push weekly for 3 weeks (weekly x 3). EU was administered at 1 mg/kg 1 h before FUra and for two additional days post-FUra therapy. The maximum tolerated doses of FUra alone were 35 and 100 mg/kg/day and for FUra plus EU were 10 and 15 mg/kg/day for the daily x 4 and weekly x 3 schedules, respectively. The dose-limiting toxicities were diarrhea and stomatitis both for FUra alone and for FUra in combination with EU. Although EU was not toxic and not active as an antitumor agent, it markedly improved the efficacy and therapeutic index of FUra. The antitumor activity of FUra was schedule dependent, yielding 13% complete and sustained tumor regression on the weekly schedule and no complete and sustained tumor regression on the daily schedule. The combination of FUra and EU produced 100% complete and sustained tumor regression on both schedules. The therapeutic index was < or = 1 for FUra alone and 6 for FUra with EU. EU was considerably more effective than either leucovorin or N-(phosphonacetyl)-L-aspartate as a modulator of FUra. Leucovorin or N-(phosphonacetyl)-L-aspartate induced minimum improvements on the daily schedule and only increased the therapeutic index to 1.5 on the weekly schedule. Because a 4-day continuous infusion of FUra alone at the maximum tolerated dose did not improve FUra therapy, we conclude that the improvements by EU involve additional modulations that complement the enhanced exposure of FUra.
Animals↗
Proliferation kinetics of recruited cells in a mouse mammary carcinoma.
Solid tumors contain populations of proliferating (P) and quiescent (Q) cells. Shifting between these populations occurs continuously and cells are recruited from quiescence to proliferate (Q-->P) as a result of exogenously applied or endogenous cell depleting stimuli. Direct measurements of the proliferation kinetics of these Q-->P cells in solid tumors are difficult to make because of the much larger percentage of P-cells. In order to specifically analyze the kinetics of the Q-->P cells, double thymidine analogue labeling was used. This was accomplished by first labeling in vivo all of the P-cells in MCaK tumors using continuous exposure to chlorodeoxyuridine (CldUrd) administered by a minipump over 21 h. About 75% of the aneuploid cells are P-cells based on CldUrd labeling. At different times after the pumps were removed, the tumors were pulse-labeled with iododeoxyuridine (IdUrd) and harvested 6 h later. A 3-color flow cytometry assay was used to simultaneously and independently analyze CldUrd and IdUrd incorporation, as well as DNA content. The Q-->P cells were identified as having only been labeled with IdUrd. The length of their S-phase was calculated from the movement of the Q-->P cells during the 6 h after IdUrd labeling. The results showed the length of S-phase for the recruited cells to be slightly, but significantly, longer than the length of S-phase for the total cells (11 h versus 9 h, respectively). Thus, the recruited cells appear to have slightly slower kinetics than the proliferating cells in the absence of a perturbing stimulus such as radiotherapy or chemotherapy.
Animals↗
Modulation of target enzyme associated with the action of antifolates.
The cytotoxicity and molecular effects of antifolate thymidylate synthase inhibitor, ICI-D1694, against human ileocecal carcinoma, were evaluated. The drug concentration for 50% inhibition of cell growth by ICI-D1694 is 73 nM and 3 nM following 2 hr and 72 hr exposure, respectively. The drug induces high level of DNA single strand breaks in a time dependent manner, but subsequent to maximum inhibition of thymidylate synthase. Drug effects can be reversed by thymidine and leucovorin at > 1 microM concentrations. Leucovorin action is primarily at the cell membrane level, competing with the transport and activation of ICI-D1694. Thymidine, however, exerts its competitive effect primarily at the level of thymidylate synthase.
Antimetabolites, Antineoplastic↗
Double labelling to obtain S phase subpopulations: application to determine cell kinetics of diploid cells in an aneuploid tumour.
We studied the cell kinetics of the murine mammary carcinoma MCa-K using iododeoxyuridine (IdUrd) and chlorodeoxyuridine (CldUrd) given at different times as independently detectable labels of S phase cells. The presence of IdUrd and CldUrd, and the amount of DNA were measured by three-colour flow cytometry making it possible to define three subpopulations within S phase and to measure the progression through the cell cycle during the time following labelling. In DNA histograms of these subpopulations, the diploid and aneuploid cells (which had a DNA index of 1.7) are essentially completely separated. From appropriate combinations of cells labelled with IdUrd only, CldUrd only, or both, it was possible to construct separate DNA distributions for the labelled diploid and aneuploid cells at the times of administration of each label. The kinetics of the diploid and aneuploid cells could be calculated for individual tumours from these two time points without having to make corrections for the presence of the second population. The diploid and aneuploid populations had indistinguishable S and G2 + M phase durations, T(S) and T(G2 + M), of about 9 and 2 h; however, the potential doubling time values for the aneuploid and diploid populations were 30.2 and 101.2 h respectively.
Aneuploidy↗