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Y M Rustum

Publications and source records attributed to Y M Rustum.

209 records · Page 12Linked to original sources
PubMedDate not supplied

Modulation of doxorubicin-induced DNA lesions by verapamil, DMDP and dipyridamole in resistant P388 cell lines.

Lymphoid cell lines resistant to doxorubicin, P388/R, were characterized by: 1) decreased intracellular acumulatin and retention of DOX; 2) decreased amount of DOX-induced DNA lesions; and 3) rapid repair of DOX-induced DNA lesions. Using the highest noncytotoxic concentrations of three modulators; 2 calcium channel blockers, Verapamil (VEP) and DMDP and a nucleoside transport inhibitor, Dipyridamole (DIP), restoration of Doxorubicin (DOX) sensitivity in vitro against P388/R cells was partial; resistance was reduced from approximately 200 to 10 fold, although DOX accumulation in the resistant cells in the presence of the modulators was completely restored. The DNA single-strand break (SSB) level induced by DOX in P388/S cells (1371 +/- 144 rad equivalents) was significantly higher than in P388/R cells (74 +/- 17 rad equivalents). The effects of VEP, DMDP and DIP on the induction of DNA SSBs by DOX in P388/R were different. DMDP and DIP potentiated the DOX-induced DNA SSBs by 30% each and VEP by 15%. Furthermore, while VEP and DIP had no significant effects on the rapid repair of DOX-induced SSBs, no significant repair of DNA lesion was observed in P388/R treated with DMDP at 1.2 microM, a non-cytotoxic concentration. These data indicate that although these modulators can effectively restore the intracellular accumulation and retention of DOX, these conditions although essential are not sufficient for the complete restoration of DOX sensitivity in this highly resistant cll line. The ability of a calcium antagonist, DMDP, to circumvent DOX resistance might be related not only to the modulation of drug retention, but also to the ability to retard the repair of DOX-induced DNA SSBs.

Alkaloids↗
PubMedDate not supplied

Enhancement of adriamycin-induced cytotoxicity by increasing retention and inhibition of DNA repair in DOX-resistant P388 cell lines with new calcium channel blocker, DMDP.

The effect of DMDP, N-(3,4-dimethoxyphenethyl)-N-methyl-2-(2-naphthyl)-m-dithiane-2-propylam ine hydrochloride, on DOX-induced cytotoxicity, drug uptake, DNA damage and repair was investigated in adriamycin sensitive and resistant P388 cell lines. In vitro, the DOX-resistant P388 cells used are about 300-fold more resistant than the sensitive cells. Resistant cells were characterized by lower DOX accumulation, rapid drug efflux, significant decrease of DNA single and double strand breaks and rapid repair of the induced single strand breaks. DMDP, a calcium channel blocker, is an effective modulator of DOX resistance in P388 cells. This modulation was found to be highly dependent of the concentration of the modulators, optimal at the maximally moncytotoxic concentrations of 1-4 microM, and the duration of exposure to the modulator, optimal under conditions of continuous exposure to the modulator. Under the optimal conditions in the presence of the modulator, DMDP, both intracellular concentration and retention of DOX were restored in the resistant P388 cells to the value comparable to those found in DOX sensitive P388 cells. Even though DOX accumulation and retention were at a comparable level in both the sensitive and resistant cells in the presence of DMDP, the amount of DNA single strand breaks achieved in the resistant cells was only about 30% of the amount of damage observed in the sensitive cells. The data indicate that if P388/R cells were only exposed to DOX for about 2 h, the induced DNA single strand breaks were repaired rapidly within 8 h thereafter, while no significant repair was seen in the resistant cells exposed to DOX in combination with DMDP. In contrast, the repair of the extensive DNA single strand breaks induced by DOX in P388/S cells was not effected by DMDP. These data clearly demonstrated that resistance to DOX in P388 cells are multifactorial. Restoration of intracellular accumulation and retention of DOX by DMDP in the resistant cells are although necessary but not sufficient for complete restoration of the sensitivity of the highly resistant cells.

Alkaloids↗
PubMedDate not supplied

Effects of DMDP, a tiapamil analogue, on adriamycin efflux in adriamycin-resistant and -sensitive P388 cells.

The calcium channel blockers 'DMDP' [N-3,4-dimethoxyphenethyl)-N-methyl-2-(2-naphthyl-m-dithane-2-prop ylamine)] and verapamil inhibited the active efflux of adriamycin from adriamycin-resistant P388 leukemia cells but had no effect on the drug-sensitive cell line. However, after removal of the calcium channel blockers, DMDP at a low drug concentration caused a much longer inhibition of this efflux pathway than verapamil. This may be attributed to the higher binding affinity of DMDP for receptor sites.

Alkaloids↗
PubMedDate not supplied

Retention of cytosine arabinoside in mouse lung following intravenous administration in liposomes of different size.

An extrusion technique was used to obtain multilamellar lipid vesicles (MLV, liposomes) of different size distribution. The larger MLV ranged in diameter from 0.1 to 2.6 mu and the smaller from 0.1 to 1.5 mu, and both were composed of phosphatidylserine/phosphatidylcholine/cholesterol in the molar ratio 1:4:5. After intravenous injection of large and small MLV containing encapsulated [3H]cytosine arabinoside (ara-C), their distribution in various organs showed that the fraction of the dose associated with lung was greater for large MLV relative to small MLV by factors of 3.6--10 after 1 hr, 5.3--14 after 4 hr, and 17--23 after 24 hr. For large MLV more than 50% of drug remaining in vivo after 24 hr was associated with the lung, compared with 2.5% for small MLV. Almost all of the 3H associated with lung at all times for both large and small MLV could be accounted for by unchanged ara-C. Differences in 3H levels between small and large MLV in other tissues were much less dramatic or were not significant. The apparent in vivo stability of the liposomes was not affected by size. The data are consistent with an initial trapping of large MLV during first passage in the lung, with subsequent binding and retention. Release of ara-C from large or small MLV in the lung is apparently slow relative to meatbolism.

Animals↗
PubMedDate not supplied

Evaluation of topoisomerase I catalytic activity as determinant of drug response in human cancer cell lines.

The prognostic value of topoisomerase I (Topo I) catalytic activity and expression of the multidrug resistance (MDR) marker P-glycoprotein (Pgp) and multidrug resistance protein (MRP) for in vitro sensitivity to Topo I interactive agents were evaluated. The efficacy of short term (2 h) and long term (24 h) exposures of camptothecin (CPT), two CPT derivatives (SN-22, SN-38) and the indolocarbazole compound NB-506, was determined against human ovarian carcinoma (A2780 and A2780 DX5), human fibrosarcoma (HT1080 and IIT1080/DR4) and human ileocecal carcinoma (HCT-8). For each cell line the Topo I protein levels and catalytic activity were determined and correlated with drug-induced cytotoxicity. In general, the Topo I protein levels correlated with Topo I catalytic activity. Drug-induced cytotoxicity increased significantly with prolongation of the exposure time. With the 2 h exposure, the multidrug resistant A2780 DX5 cell line (Pgp+, MRP-) was moderately resistant to all four drugs compared to its parental cell line. In case of CPT and SN-22 but not for SN-38 and NB-506, this resistance was no longer detectable following 24 h drug exposure. No resistance was detectable for the multidrug resistant HT1080/DR4 (Pgp-, MRP+) cell line when compared to its parental cell line. With short term exposures a strong trend was observed toward increased cytotoxicity with increased Topo I catalytic activity, especially if this correlation was studied between derivative cell lines (A2780 vs. A2780 DX5 and HT1080 vs. HT1080/DR4). This correlation weakened when all 5 cell lines and both exposure conditions were considered. Thus, although overall the correlation between Topo I catalytic activity and sensitivity to Topo I interactive drugs between different cell lines is weak, this correlation may be stronger when comparing derivative cell lines. For CPT and SN-22 but not for SN-38 and NB-506, the moderate resistance levels observed in the Pgp-expressing cell line could be negated by prolongation of exposure duration. MRP expression did not effect drug efficacy. The data demonstrate that the importance of Topo I catalytic activity as single prognostic factor for drug response to Topo I interactive agents is weak and that additional mechanisms affecting drug response have to be taken into consideration.

Antineoplastic Agents, Phytogenic↗
PubMedDate not supplied

Rationale for treatment design: biochemical modulation of 5-fluorouracil by leucovorin.

Preclinical in vitro and in vivo results have demonstrated the conditions required for optimal modulation of 5-FU activity by LV. The ability to increase intracellular concentrations of higher chain length polyglutamates was a function of duration of longer exposure to LV rather than the dose. In rats bearing advanced colorectal tumors, the role of LV dosage was more clearly evident with the weekly 5-FU treatment schedule than with the daily schedule. Phase III clinical trials in patients with advanced colorectal cancer demonstrated that low-dose and high-dose LV (daily x 5) and weekly high-dose LV schedules yielded similar response rates with different toxicity profiles. A phase III trial demonstrated significant therapeutic advantages for a bimonthly schedule of high-dose LV over a monthly schedule of low-dose LV. Taken together, these results provide insight into LV biomodulation, but the optimal conditions for these regimens for individual patients remain undetermined. To date it has not been possible to identify the optimal conditions for modulation of 5-FU by LV in individual patients with advanced colorectal cancer, and response rates are comparable. A regimen that offers the opportunity to manage treatment-induced toxicity is recommended. With diarrhea being the primary dose-limiting toxicity with the weekly 5-FU and high-dose LV (manifested during the 2-3 weeks of treatment), management of toxicity can be achieved by delaying treatment, by dose reduction, and/or by treatment with octreotide47 without compromising efficacy. In contrast, with the daily x 5 schedule, multiple toxicities (mucositis [stomatitis], diarrhea, neutropenia, and hand and foot syndrome) are manifested regardless of the dose of LV administered. An additional advantage to the weekly schedule is that it provides the opportunity to use 5-FU/LV treatment in sequence or combination with other drugs, such as topoisomerase I inhibitors (CPT-11), antifolates (methotrexate, trimetrexate), and platins (oxaliplatin).

Animals↗
PubMedDate not supplied

Topoisomerase-I inhibitor SN-38 can induce DNA damage and chromosomal aberrations independent from DNA synthesis.

BACKGROUND: SN-38 is the active metabolite of the topoisomerase-I (topo-I) inhibitor Irinotecan (CPT-11). Generally, topo-I inhibitors stabilize the complex between topo-I and DNA which collide with moving DNA replication forks, eventually leading to double stranded DNA damage. Therefore, topo-I inhibitors are regarded as S-phase specific. The present study investigated S-phase dependent and independent effects of SN-38. MATERIALS AND METHODS: Effects of exposure of A2780 cells to SN-38 (2 hours) were studied by assessing DNA/protein crosslinks, DNA damage and cytogenetic aberrations. RESULTS: A close correlation (r2 = 0.97) was established between drug-induced DNA/protein crosslinks and double stranded DNA breaks. Cytogenetic analysis revealed near maximum clastogenic effects already evident immediately following 2 hours drug exposure. However, qualitatively, chromatid breaks at 24 hours were different from those at 0 hours, in that at 24 hours they were associated with radial chromosome configurations and sister chromatid exchanges. CONCLUSION: The data corroborate that the S-phase dependent mechanism of action of topo-I inhibitors is also applicable to SN-38. The cytogenetic data indicate two distinct interactions of SN-38 with DNA: immediate induction of chromatid breaks independent from DNA synthesis, and induction of chromatid breaks associated with radial chromosome configurations dependent on DNA synthesis.

Camptothecin↗