Biomedical subjects

R M Schultz

Publications and source records attributed to R M Schultz.

274 records · Page 16Linked to original sources

PubMedDate not supplied

Sequence dependence of Alimta (LY231514, MTA) combined with doxorubicin in ZR-75-1 human breast carcinoma cells.

Alimta is a new-generation antifolate with inhibitory activity against multiple enzymes, including thymidylate synthase, glycinamide ribonucleotide formyltransferase and dihydrofolate reductase. Alimta is undergoing broad phase II evaluation as a single agent, and preliminary results show responses in several tumor types, including breast carcinoma. Doxorubicin is often used in combination chemotherapy of breast cancer. Because the two drugs have mechanisms of action that might be complementary, we investigated a possible synergism between doxorubicin and Alimta on growth inhibition of ZR-75-1 human breast carcinoma cells. Cytostatic activity was evaluated using semi-automated MTT assays, and drug interactions were determined using CalcuSyn (Chou/Hayball) multiple drug effect analyses. The cells were exposed to Alimta or doxorubicin as single agents and combinations for 24 hours starting at the time of plating or for 72 hours starting 24 hours after plating with a total culture time of 96 hours. Preincubation with Alimta for 24 hours followed by exposure to doxorubicin for 72 hours resulted in highly synergistic activity, whereas the opposite sequence or simultaneous exposure produced mainly an additive response. DNA flow cytometry studies indicated that Alimta causes a build-up of cells near the G1/S interface after 24 hours of incubation. The data suggest that, to obtain maximal antitumor activity, Alimta should precede doxorubicin when the drugs are given in combination chemotherapy protocols.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

In vitro and in vivo antitumor activity of the phosphatidylinositol-3-kinase inhibitor, wortmannin.

The microbial product wortmannin has previously been shown to be a potent inhibitor of phosphatidylinositol-3-kinase. In view of the potential role of this enzyme in transduction of mitogenic signals, we determined the cytotoxic activity of wortmannin against several human tumor cell lines in vitro. The most sensitive lines included GC3 colon carcinoma, IGROV1 ovarian carcinoma, and CCRF-CEM leukemia (IC-50s ranging from 0.7-2.1 microM). The cytotoxicity of wortmannin was decreased approximately 10-fold by serum-free conditions. Wortmannin was generally less active in low passage human breast cancer cell lines that overexpress either epidermal growth factor receptor or Her2/neu. Wortmannin was also tested for in vivo antitumor activity against seven murine tumor and ten human tumor xenograft models. Activity (> 60% inhibition of tumor growth) was observed in only the C3H mammary carcinoma and the human BxPC-3 pancreatic carcinoma xenograft. In vivo antitumor activity did not correlate with in vitro sensitivity to wortmannin cytotoxicity.

Androstadienes↗

PubMedDate not supplied

Effect of albumin on antitumor activity of diarylsulfonylureas.

Several diarylsulfonylureas (DSU), including Sulofenur (LY186641) and LY181984, have been described that exhibit wide spectrum and high therapeutic activity against murine solid tumors and human tumor xenografts. The mechanism for antitumor activity is poorly understood. Moreover, in vitro cytotoxic activity in serum-containing medium is not predictive of in vivo antitumor activity for DSU. Since DSU are extensively bound to serum albumin (> 99%), we sought to determine the effect of albumin on tumor cytotoxicity. We adapted human CCRF-CEM leukemia and GC3 colon carcinoma cells for growth in UltraCHO serum- and albumin-free medium. In comparisons between normal growth medium (RPMI-1640 with 10% fetal bovine serum) and UltraCHO medium, the unbound fraction of drug correlated better with cytotoxic activity than did the total drug. Tumor cytotoxicity by DSU required > 24 h and was markedly enhanced in UltraCHO medium. For example, LY181984 and Sulofenur had IC50 values of 7.4 and 12.1 micrograms/ml against CCRF-CEM in normal growth medium and 0.6 and 0.2 microgram/ml in UltraCHO. Moreover, DSU with the lowest IC-50s in albumin-free medium displayed the most potent in vivo antitumor activity in the 6C3HED lymphosarcoma. A Sulofenur-resistant CCRF-CEM cell line was developed by culturing the cells for > 20 passages in UltraCHO medium containing LY186641 at 2 micrograms/ml (10X IC-50). This line showed approximately 18-fold resistance to LY186641, but did not show cross-resistance to vinblastine, actinomycin D, or doxorubicin. The albumin-free conditions may be useful for further mechanistic studies on the antitumor action by DSU. Further studies are underway to determine whether DSU structural requirements for cytotoxicity an albumin binding are intrinsically linked.

Animals↗

PubMedDate not supplied

Role of folic acid in modulating the toxicity and efficacy of the multitargeted antifolate, LY231514.

We studied the effects of folic acid on modulating the toxicity and antitumor efficacy of LY231514. Using several human tumor cell lines adapted to growth in low folate medium, folic acid was shown to be 100- to 1000-fold less active than folinic acid at protecting cells from LY231514-induced cytotoxicity. The lethality of LY231514 was compared in mice maintained on standard diet or low folate diet. The LD50 occurred at 60- and 250-fold lower doses of LY231514 in DBA/2 and CD1 nu/nu mice, respectively, maintained on low folate diet compared to standard diet. The L5178Y/TK-/HX-murine lymphoma was much more sensitive to the antitumor action of LY231514 compared to wild type L5178Y-S tumors. For mice on low folate diet, LY231514 at 0.3 and 1 mg/kg (qd x 10, i.p.) produced 100% inhibition of L5178Y/TK-/HX-lymphoma growth, and significant lethality occurred at > or = 3 mg/kg. For mice on standard diet, LY231514 produced > 95% inhibition of tumor growth at 30 to 300 mg/kg, but all mice died at 800 mg/kg. Folic acid supplementation was demonstrated to preserve the antitumor activity of LY231514 while reducing toxicity. The combination of folic acid with LY231514 may provide a mechanism for enhanced clinical antitumor selectivity.

Animals↗