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Biomedical subjects

A Sobrero

Publications and source records attributed to A Sobrero.

At least 55 records · Page 3Linked to original sources
PubMed1992

Phase II study of 5-fluorouracil plus leucovorin and interferon alpha 2b in advanced colorectal cancer.

15 untreated patients with advanced measurable colorectal cancer along with other 29 patients in progression after failing first line chemotherapy with fluoropyrimidines received 5-fluorouracil (5FU) 500 mg/m2 given as a weekly bolus at mid-infusion of leucovorin (LV), 500 mg/m2 administered intravenously over 2 h and interferon alpha 2b (IFN) 3 x 10(6) U given intramuscularly every other day. All patients had their previous chemotherapy at least 4 weeks prior to 5FU-LV-IFN. 5 patients discontinued the three drug regimen due to toxicity (intense weakness, fever and influenza-like symptoms in 4 patients; diarrhoea in 1 patient) however no grade IV toxicity was observed. IFN administration was reduced to twice/weekly in 5 patients due to influenza-like symptoms. 1 complete response and 5 partial responses were observed (13.6% response rate); the complete response was obtained in a patient resistant to 5FU: the response rate was only twice as much in untreated patients (3/15 patients, 20%) compared with that in patients previously treated with fluoropyrimidines (3/29 patients, 10.3%). Therefore, modulation of 5FU with LV plus IFN at the doses and schedules employed in this study may rarely overcome clinical resistance to the fluoropyrimidine and the addition of IFN does not appear to enhance the activity of 5FU plus LV.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Rapid development of resistance to antifolates in vitro: possible clinical implication.

Within three repeated 7-day incubation periods with either methotrexate (MTX) or trimetrexate (TMTX), human colon adenocarcinoma cells (HCT-8) developed high levels of resistance to these drugs, as evidenced by approximately 20- and 50-fold increases, respectively, in the median effective doses. Similarly, within six short-term exposures (4 hours) to the same drugs, a high degree of resistance developed in the cells. Alternating 4-hour treatment cycles with MTX and TMTX did not delay the onset of resistance to these antimetabolites in the HCT-8 cells. The same strategy produced no better results than giving either MTX or TMTX alone to (C57BL/6 x DBA/2)F1 mice bearing murine leukemia P388 cells. Furthermore, HCT-8 cells resistant to short-term (4-hour) exposure to MTX were cross-resistant to the same drug given for 7 days continuously, and cells resistant to MTX given continuously for 7 days were cross-resistant to the same drug given for 4 hours. Analogous results were obtained with TMTX, indicating that, under these circumstances, changing the schedule of administration of the same agent does not overcome resistance to it. The clinical relevance of these data to prolonged adjuvant chemotherapy, as well as loco-regional and continuous-infusion chemotherapy, is discussed.

Adenocarcinoma↗
PubMed1990

Improved therapeutic index of cisplatin by procaine hydrochloride.

The local anesthetic procaine hydrochloride (P.HCl) had little effect on the sensitivity of P388 leukemic cells to cisplatin (DDP) in vitro, but the simultaneous administration of DDP and P.HCl (40 mg/kg) to BDF1 mice produced 50% lethal dose (LD50) and 90% lethal dose (LD90) values approximately two times higher than those observed with DDP alone. DDP-P.HCl diluted in water and administered intraperitoneally (IP) on day 1 and on days 1 and 5 to BDF1 mice bearing P388 leukemic cells produced 33% and 50% cure rates, respectively, at the maximum tolerated dose (16 mg/kg for the single administration and 10 mg/kg given on days 1 and 5). In contrast, under the same conditions, the cure rates obtained with DDP alone (10 mg/kg for the single administration and 8 mg/kg given on days 1 and 5) were 17% and 9%, respectively. Protection from DDP nephrotoxicity seems to be the explanation for the higher doses of DDP that mice can tolerate when DDP is given simultaneously with P.HCl. In fact, the increased blood urea nitrogen (BUN) levels observed 4-7 days following a single IP administration of DDP (8 or 16 mg/kg), as well as the tubular degenerative changes detected by light microscopy, were not observed when the same doses of DDP were given simultaneously with P.HCl. Since DDP nephrotoxicity is known to be reduced when the drug is diluted in 0.9% NaCl solution, we compared the combinations DDP-P.HCl in water, and DDP and DDP-P.HCl in 0.9% NaCl solution. The antitumor activity of DDP diluted in water and administered with P.HCl was similar to that observed in mice treated with DDP alone diluted in 0.9% NaCl solution. However, further improvement of the therapeutic index was achieved after the administration of DDP-P.HCl diluted in 0.9% NaCl solution; this regimen produced a cure rate of 67% (12 of 18 animals). The clinical relevance of these findings is strengthened by the observation that similar results were obtained when P.HCl was given by the intravenous route.

4-Aminobenzoic Acid↗
PubMed1990

Resistance to 5-fluorouracil and 5-fluoro-2'-deoxyuridine mechanisms and clinical implications.

Preliminary to studies on biopsy specimens from colorectal carcinomas, we have investigated the mechanisms of resistance to 5-fluorouracil (FUra) and 5-fluoro-2'-deoxyuridine (FdUrd) on a human colon carcinoma cell line, HCT-8 in vitro. After obtaining a high level of resistance, extracts were made from sensitive and resistant HCT-8 cells and the enzymes responsible for the activation or catabolism of fluoropyrimidines were assayed using a thin-layer chromatographic method. The activity of thymidine-kinase, thymidine phosphorylase, uridine-kinase, uridine phosphorylase, orotate phosphoribosyl transferase as well as the activity of the target enzyme thymidylate synthase were not significantly different in sensitive, FUra resistant or FdUrd resistant cells. The activities of these enzymes in sensitive HCT-8 cells were respectively 15.6, 3.4, 40.8, 2.1, 6.9 and 30.2 nmol/mg protein/h. Direct evidence that impaired transport was the mechanism of resistance to FdUrd was obtained using a short term "oil stop" technique, whereas indirect evidence suggests that reduced inhibition of thymidylate synthase is likely to be the mechanism of resistance to FUra. Cells seven hundred-fold resistant to FdUrd were in fact still sensitive to FUra (ED50 value after continuous exposure 2.1 microM) while FUra resistant cells were fully cross-resistant to FdUrd (ED50 value after continuous exposure 0.003 microM). The clinical relevance of these data is discussed in the light of the extensive literature about the potentiation of fluoropyrimidines by leucovorin.

Colonic Neoplasms↗
PubMed1989

Sequence-dependent enhancement of HCT-8 cell kill by trimetrexate and fluoropyrimidines: implications for the mechanism of this interaction.

The new folate antagonist trimetrexate is an inhibitor of dihydrofolate reductase, but unlike methotrexate (MTX) it is not polyglutamylated. We have compared the cell killing effects of MTX and trimetrexate/5-fluorouracil (FUra) and 5-fluoro-2'-deoxyuridine (FdUrd) combinations on HCT-8 cells in vitro, in an attempt to explore indirectly the role of polyglutamylation of the antifol in determining the known sequence-dependent synergism between MTX and FUra. The comparisons were made in a number of equitoxic concentrations and times of exposure. Trimetrexate given for 4, 24 or 48 h followed by FUra, for 4, 24 or 196 h, produced synergistic HTC-8 cell kill, whereas antagonism was observed when FUra preceded or was given simultaneously with trimetrexate. The degree of interaction was essentially identical to those obtained when MTX was combined with FUra. The interactions between MTX/FdUrd and trimetrexate/FdUrd were also similar: synergistic cell kill resulted from the sequences trimetrexate or MTX followed by FdUrd, while additive effects were produced by trimetrexate or MTX + FdUrd combinations or FdUrd followed by MTX or trimetrexate. Because the same interactions observed with MTX/FUra or FdUrd combinations were also obtained when trimetrexate was combined with the fluoropyrimidines, it is unlikely that polyglutamylation of the antifols plays a significant role in determining the different sequence-dependent effects of these antimetabolites. However, these studies do not rule out the possibility that increased levels of dihydrofolate polyglutamates increase fluoropyrimidine cytotoxicity.

Adenocarcinoma↗
PubMed1987

Design and rationale for novel antifolates.

The goals of new antifolate development are: 1) improved selectivity, 2) improved penetration into pharmacologic sanctuaries, and 3) effectiveness vs. tumors either with intrinsic or acquired resistance to methotrexate (MTX). The major target for antifolate development has been dihydrofolate reductase (DHFR), but other critical folate-dependent enzymes, i.e., thymidylate synthase, methionine synthetase, and folylpolyglutamate synthetase are also important targets for new antifolate development. The possibility that DHFR from tumor tissue differs significantly from normal tissue DHFR now seems improbable, and the ideas of the late Bill Baker to design specific inhibitors of the tumor enzyme vs. the normal tissue DHFR are unlikely to succeed. However, the experience with triazinate (Baker's antifol; TZT) indicates that transport of antifols could be exploited to provide selective toxicity, as well as to provide agents effective vs. MTX-resistant cells. This work led to a second generation of "nonclassical" folate antagonists, of which trimetrexate (JB-11; TMQ) is now in clinical trial. Uptake of TMQ is via an MTX-independent membrane system, and extremely high intracellular levels of this drug are achieved in human leukemia cells.

Animals↗
PubMed1985

Methotrexate resistant cells as targets for selective chemotherapy.

Strategies that are selective for eradicating methotrexate resistant cells are described. These strategies have been developed based on knowledge of the mechanism of drug resistance encountered in experimental systems and in the clinic. Drug resistance to methotrexate in experimental tumors is commonly due to either gene amplification (dihydrofolate reductase) or to impaired transport of methotrexate. While no effective drugs or methods to prevent gene amplification have been described, the concept of developing "pro drugs", i.e. a drug that is selectively reduced by dihydrofolate reductase to an inhibitor of another critical folate enzyme (thymidylate synthase, methionine synthetase, folylpolyglutamate synthetase) remains worthwhile. Second generation antifolates such as trimetrexate which are effective vs methotrexate transport resistant cells have already been developed and are in clinical trial.

Animals↗
PubMed1984

Leucovorin protection on pluripotent hemopoietic stem cells in mice treated with high-dose methotrexate.

Haematologic effects of delayed 16 h administration of leucovorin (LV) following high-dose methotrexate (HDMTX) were analyzed in C57Bl X C3H F1 mice. Results show that 16 h administration of LV significantly reduces the toxic effects of HDMTX on hemopoietic progenitors and bone marrow cells. At 12 days after HDMTX administration, the bone marrow level of CFUs was significantly higher in HDMTX-LV treated mice than in HDMTX treated animals. In comparison with previous data obtained when LV was injected 2 h after HDMTX, the delay in administration of LV does not appear to reduce the protective effect of the vitamin.

Animals↗
PubMed1982

Studies on hemopoietic stem cells in mice treated with testosterone propionate and anticancer drugs.

The alleged possibility that testosterone propionate (TP) has a protective effect on hemopoietic cells submitted to the damaging effect of antitumoral drugs was studied. The bone marrow content and the proliferating fraction of CFUs were determined following a single dose on 450 mg/kg of TP. At selected times after TP injection (2 and 4 days), TP-treated mice received a single dose of azathioprine, hydroxyurea, vinblastine, cyclophosphamide, BCNU and doxorubicin. The bone marrow of CFUs were determined 24 h after drug administration. The CFUs-surviving fraction in all cases appeared similar to or lower than that found in controls not treated with TP. It seems therefore that in this experimental setting TP does not reduce the toxic effect of anticancer drugs on hemopoietic pluripotent stem cells. However, this finding does not exclude a possible protective effect of TP at different levels of hemopoiesis or when the steroid is administered with a different schedule.

Animals↗
PubMed1982

Activity of 4'-epi-doxorubicin on normal hematopoietic precursor cells in mice.

The effects of 4'epi-doxorubicin (4'-epi-DX) on survival of in situ murine bone marrow hematopoietic precursor cells (HPC) were studied. The drug was given to (C57BL X C3H)F1 mice in increasing single doses, in repeated administration (three time in 5 days), or for a long period (twice a week for 10 weeks). Survival of colony-forming units (CFUs, spleen; CFUc, culture; and CFUe, erythroid) was assayed by in vivo and in vitro methods; dose survival curves were exponential. It appears that single doses of 4'epi-DX have a greater impact on murine HPC than single doses of the parent compound. Following repeated administrations, pluripotential stem cells recover better after the derivative than after its parent drug. During prolonged treatment, the bone marrow content of committed progenitors is depleted to a lesser extent in the animals treated with 4;-epi-DX than in those receiving DX. It is, however, possible that, following the same prolonged treatment, this difference is minimal. The conclusion, these experimental data seem to indicate that 4'-epi-DX has lower toxicity in murine HPC than DX and that this is evident mainly after repeated administrations for a short period of time.

Animals↗
PubMed1982

Effects of high-dose methotrexate and leucovorin on murine hemopoietic stem cells.

This study compares the effects of a high dose of methotrexate (HDMTX) to that of a high dose of methotrexate plus leucovorin protection on the hemopoietic stem cells in a murine model. C57BL X C3H F1 mice were treated with a single large bolus (500 mg/kg body weight) of methotrexate or with the same dose of the drug plus leucovorin administered in fractionated doses during the following 24 hr. At 1 to 2 days after the administration of HDMTX, there was a large bone marrow and spleen depopulation of pluripotent stem cells and of committed and recognizable progenitors. At 2 to 3 days, a severe fall of white blood cells and reticulocytes ensued. The recovery process of hemopoietic precursors followed alternate phases of overshooting and secondary falls. Leucovorin administration appeared to protect all stages of hemopoiesis and prevented the severe drops of bone marrow cellularity and stem cell content which followed the HDMTX bolus. However, the effect of leucovorin on peripheral blood cell reduction was less significant. After treatment with HDMTX, the recovery of bone marrow cells and the burst of splenic hemopoietic activity followed a pattern similar in both leucovorin-protected and unprotected animals, but in the former, the increase in stem cells and hemopoietic progenitors appeared to reach higher values and to last longer. In particular, the overshooting of colony-forming units, culture and erythroid, reached a higher peak in leucovorin-treated mice and was more prolonged. Our results indicate that, in HDMTX-treated mice, leucovorin protection involves the earliest stages of hemopoiesis, assuring the maintenance of a satisfactory endowment of stem and progenitor cells.

Animals↗