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T S Herman

Publications and source records attributed to T S Herman.

At least 37 records · Page 2Linked to original sources
PubMed1994

Minocycline as a modulator of chemotherapy and hyperthermia in vitro and in vivo.

We tested the ability of the collagenase-inhibitor minocycline to increase the effectiveness of CDDP, BCNU and mitomycin C +/- hyperthermia. When tested in vitro in FSaIIC fibrosarcoma cells, exposure to minocycline (100 microM for 24 h) decreased the CDDP cytotoxicity at 37 degrees C and pH 7.40 in both normally oxygenated and hypoxic cells and decreased the cytotoxicity of CDDP at 42 degrees C or 43 degrees C in normally oxygenated cells while increasing the killing in hypoxic cells. When tested at pH 6.45, the presence of minocycline tended to protect both normally oxygenated and hypoxic cells from the cytotoxic effects of CDDP +/- hyperthermia. With exposure to BCNU, minocycline markedly protected both normally oxygenated and hypoxic cells at 37 degrees C at both pHs. As the temperature during the exposure to BCNU was increased to 42 degrees C or 43 degrees C, the protection afforded by minocycline diminished especially under low pH conditions where BCNU plus 43 degrees C was extremely cytotoxic to both normally oxygenated and hypoxic cells. One hour exposure to mitomycin C was more cytotoxic to hypoxic than normally oxygenated cells under all conditions of pH and temperature tested and the cytotoxicity of mitomycin C under each condition was increased by minocycline. Both CDDP and BCNU were much more cytotoxic toward FSaIIC tumors in vivo when drug administration was followed by local heating (43 degrees C, 30 min) of the tumor bearing limb. In each case, treatment with minocycline had little effect on tumor-cell killing. Treatment with mitomycin C and hyperthermia resulted in additive tumor-cell killing, and minocycline administration further increased that effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Therapeutic effect of infused Fluosol-DA/carbogen with ephedrine, flunarizine, or nitroprusside.

UNLABELLED: The perfluorochemical emulsion Fluosol-DA plus carbogen breathing has been shown to increase the effectiveness of radiation therapy in preclinical solid tumors when the emulsion was administered by i.v. bolus injection. Much of the enhancement in tumor radiation response was lost when the emulsion was administered slowly. PURPOSE: We hypothesized that an increase in tumor perfusion resulted when Fluosol-DA was administered rapidly. METHODS AND MATERIALS: In the present study, the alpha/beta agonist ephedrine, the Ca2+ channel blocker flunarizine and the nitric oxide producing vasodilating drug nitroprusside have been tested. RESULTS: Ephedrine administration resulted in a decrease in the radiation plus Fluosol-DA +/- carbogen antitumor effects in both the Lewis lung carcinoma and FSaIIC tumor systems. In contrast, flunarizine administration resulted in an increase in the efficacy of the radiation plus carbogen and the radiation plus Fluosol-DA/carbogen in both tumor systems. Even with flunarizine administration Fluosol-DA delivered slowly was less effective than when the emulsion was given rapidly. Flunarizine with Fluosol-DA infused i.v. over 30 min followed by carbogen breathing prior to and during radiation therapy resulted in a 1.7-1.6-fold increase in response compared with 2.4-2.2-fold with Fluosol-DA administered by injection i.v. and carbogen breathing prior to and during radiation therapy using growth delay of the Lewis lung carcinoma. The effects of nitroprusside were complex. This drug had considerably more effect at 10 Gy than at higher radiation doses. CONCLUSION: These studies suggest that Fluosol-DA given by i.v. injection may increase tumor perfusion and that a drug like flunarizine may be beneficial if the Fluosol-DA is administered slowly followed by carbogen breathing and radiation therapy.

Administration, Inhalation↗
PubMed1993

Modulation of antitumor alkylating agents by novobiocin, topotecan, and lonidamine.

Topoisomerase I and topoisomerase II allow a metabolically active cell to mobilize its supercoiled chromosomal DNA and undergo replication, transcription, recombination, and repair. Several topoisomerase inhibitors have recently been shown to be active in preclinical systems. Topotecan (SK&F 104,864), a water-soluble camptothecin analog, is an inhibitor of topoisomerase I. Novobiocin is an inhibitor of topoisomerase II. Lonidamine depletes cellular adenosine 5'-triphosphate (ATP) and may impede energy-dependent DNA repair, MCF-7 human breast-cancer cells were treated in vitro with topotecan, novobiocin, and lonidamine alone, in paired combinations, and in combination with CDDP and melphalan. The three enzyme inhibitors alone and in combination did not increase tumor cell sensitivity to CDDP. However, the combinations of topotecan/novobiocin and lonidamine/novobiocin did enhance the cytotoxicity of melphalan. Mice bearing the FSaII fibrosarcoma were treated in vivo with topotecan, novobiocin, and lonidamine alone, in paired combinations, and in combination with CDDP, melphalan, BCNU, and cyclophosphamide. The combination of topotecan/novobiocin had the greatest impact on tumor cell sensitivity to each cytotoxic agent tested in both tumor cell-survival and tumor growth-delay assays. This sensitization was greatest at the highest concentrations of the cytotoxic agent tested. Combinations of topoisomerase I and topoisomerase II inhibitors may be useful as modulators of antitumor alkylating agents.

Adenocarcinoma↗
PubMed1993

Addition of a topoisomerase I inhibitor to trimodality therapy [cis-diamminedichloroplatinum(II)/heat/radiation] in a murine tumor.

The cytotoxicity of the topoisomerase I inhibitors, camptothecin and topotecan, toward exponentially growing EMT-6 murine mammary carcinoma cells under various conditions of oxygenation, pH and temperature was assessed. Under normal pH (pH 7.40) conditions both camptothecin and topotecan were more cytotoxic toward normally oxygenated cells. Both agents were more cytotoxic under acidic pH (pH 6.45) and the differential in cytotoxicity due to the cellular oxygenation level disappeared. Neither camptothecin nor topotecan was enhanced in cytotoxicity by hyperthermia (42 degrees C or 43 degrees C, 60 min) during drug exposure. Both camptothecin and topotecan killed increasing numbers of FSaIIC tumor cells with increasing dose of the drugs in vivo in a log/linear manner. Local hyperthermia (43 degrees C, 30 min) increased the tumor cell killing of the drugs but decreased the toxicity of these agents to the bone marrow granulocyte/macrophage-colony-forming units. Topotecan was a more effective modulator of cisplatin than was camptothecin, as determined by FSaIIC tumor cell survival assay and by FSaIIC tumor growth delay. Although both camptothecin and topotecan were effective additions to a treatment regimen including cisplatin and daily fractionated radiation (5 x 3Gy), neither of these topoisomerase I inhibitors increased the tumor growth delay produced by the trimodality regimen of cisplatin/hyperthermia/radiation.

Animals↗
PubMed1992

Enhancement of alkylating agent activity by SR-4233 in the FSaIIC murine fibrosarcoma.

BACKGROUND: The most commonly used antineoplastic drugs are more cytotoxic toward normally oxygenated tumor cells than toward hypoxic tumor cells. PURPOSE AND METHODS: To examine the ability of SR-4233, a new cytotoxic agent, to overcome the resistance of hypoxic tumor cells to antitumor alkylating agents, we tested the cytotoxic effect of SR-4233 alone and in combination with varying doses of cisplatin (CDDP), cyclophosphamide (CPM), carmustine (BCNU), or melphalan (L-PAM) on tumor cells and bone marrow cells isolated from C3H/FeJ mice bearing the FSaIIC fibrosarcoma. RESULTS: When SR-4233 alone was given, tumor cell killing was limited. When SR-4233 was administered just before single-dose treatment with CDDP, CPM, BCNU, or L-PAM, however, marked dose enhancement leading to increased cytotoxic effects on tumor cells and on bone marrow cells was observed. Similar experiments with tumor cell subpopulations, selected by Hoechst 33342 dye diffusion, confirmed that while cytotoxicity to both bright (oxygenated) and dim (hypoxic) cells was increased by combining each alkylating agent with SR-4233, the enhancement of the effect was relatively greater in the subpopulation of dim cells. The delay in the growth of tumors in animals treated with the combination of SR-4233 and CDDP, CPM, or L-PAM was 1.6-fold to 5.3-fold greater than that in animals treated with each alkylating agent alone. CONCLUSION: Our results suggest that SR-4233 may have the potential to improve the clinical efficacy of commonly used antitumor alkylating agents.

Alkylating Agents↗
PubMed1992

24-hour efficacy of once-daily diltiazem in essential hypertension.

The safety and effectiveness of a once daily formulation of diltiazem hydrochloride (diltiazem CD) in the treatment of essential hypertension was assessed in a total of 127 patients with supine diastolic blood pressures (DBP) of 95 to 110 mmHg randomized to diltiazem CD (n = 61) or placebo (n = 66). Patients were titrated to doses of 120, 240, or 360 mg to achieve DBP reduction to less than 90 mmHg. At end study diltiazem CD changed trough supine SBP and DBP by -8.4 +/- 1.7 (p = 0.0009) and -8.6 +/- 1.1 mmHg (p = 0.0075), respectively. Heart rate was not significantly changed (-1.3 +/- 1.1 beats/min, p = 0.4362). The average dose of diltiazem CD was 268 mg with 69% achieving a clinical response. A subset of 47 patients underwent ambulatory blood pressure monitoring to assess the consistency of the effect over the full 24-h dosing interval. Diltiazem CD lowered DBP and SBP throughout the dosing interval. The overall side effect profile was similar to placebo. This study provides evidence of 24-h efficacy of this new, once daily formulation of diltiazem.

Adolescent↗
PubMed1992

Dose-dependent effects of betaxolol in hypertension: a double-blind, multicenter study.

This study determined the dose-response relationship among three doses of betaxolol compared with placebo in patients with mild-to-moderate hypertension. In this double-blind, placebo-controlled trial, 317 hypertensive patients were randomly assigned to receive placebo or betaxolol 5, 10, or 20 mg once daily for 4 weeks. A significant (P less than .05) decrease in supine diastolic blood pressure (BP) compared with concurrent placebo was evident with all three doses of betaxolol after 1 week of active treatment. Each dose of betaxolol maintained a significant reduction in diastolic and systolic BP and heart rate responses throughout the 4-week treatment period. At the fourth week (final treatment evaluation), BP and heart rate were significantly (P less than .05) reduced by all three doses of betaxolol compared with placebo. For supine systolic and diastolic BP, the decreases with betaxolol 20 mg were significantly (P less than .05) greater than with the 5 mg dose, but there was no statistically significant difference between the 10-mg and either the 5- or 20-mg doses. For standing diastolic BP, the effect of betaxolol 5 mg once daily was significantly (P less than .05) less than that of 10 and 20 mg. The overall supine diastolic BP response to betaxolol was dose dependent, and more patients responded to the 10- and 20-mg doses of betaxolol (66% and 76%, respectively) than to the 5-mg dose (59%). For each efficacy variable, the absolute magnitude of the reduction was greater with increasing dose. In subgroup analyses, BP responses were analyzed by race, age, baseline BP, and age combined with baseline BP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Beta-carotene and/or vitamin E as modulators of alkylating agents in SCC-25 human squamous carcinoma cells.

Dietary levels of beta-carotene and vitamin E have been associated with cancer prevention and to a lesser extent, with therapeutic enhancement of cancer treatment. We report on the cytotoxicity of beta-carotene, vitamin E, and the combination of beta-carotene and vitamin E in human SCC-25 squamous carcinoma cells under various environmental conditions found in solid tumor masses. Beta-Carotene was selectively cytotoxic toward normally oxygenated cells and was generally more cytotoxic at normal pH than at acidic pH (6.45). Vitamin E was selectively cytotoxic toward normally oxygenated cells following 6 h exposure at normal pH and was generally equally cytotoxic toward normally oxygenated and hypoxic cells under the other conditions tested. Beta-Carotene was an effective modulator of cisplatin (CDDP) cytotoxicity toward SCC-25 cells, whereas vitamin E was not. Both beta-carotene and vitamin E were effective modulators of melphalan cytotoxicity toward SCC-25 cells. Treatment of SCC-25 cells with beta-carotene (70 microM, 2h) resulted in a reduction in superoxide dismutase activity, in glutathione-S-transferase activity, and in nonprotein sulfhydryl levels in the cells. Exposure to vitamin E or to a combination of beta-carotene and vitamin E increased the glutathione-S-transferase activity in SCC-25 cells by 40%-45% over the control value. Treatment with beta-carotene, vitamin E, or canthaxanthin reduced the incorporation of [3H]-thymidine into SCC-25 cells but not that into normal human keratinocytes. The most marked reduction in [3H]-thymidine incorporation into SCC-25 cells occurred following treatment with the combination of beta-carotene and melphalan. We hope to continue to explore the mechanisms of this effect and to study these combinations in vivo.

Alkylating Agents↗
PubMed1992

Minocycline in combination with chemotherapy or radiation therapy in vitro and in vivo.

In the present study the potential of minocycline, a semisynthetic tetracycline that inhibits collagenase activity in vivo, as an adjuvant to standard anticancer therapies was explored in vitro and in vivo. In EMT-6 cells, minocycline proved to be only minimally cytotoxic, producing a 50% cell kill at concentrations of 132 and 220 microM in normally oxygenated and hypoxic cells, respectively, after 24 h exposure to the drug. In vitro, there appeared to be no interaction between minocycline and cisplatin (CDDP), melphalan, 4-hydroperoxycyclophosphamide, or radiation. In tumor-cell survival studies using the FSaIIC murine fibrosarcoma, short-term treatment with minocycline (5 x 5 mg/kg given over 24 h) was only minimally cytotoxic and did not alter the tumor response to a range of radiation doses. However, when minocycline (5 x 5 mg/kg given over 24 h) was added to treatment with cyclophosphamide, there was a 4-fold increase in FSaIIC tumor-cell killing across the dose range of cyclophosphamide doses tested, whereas the killing of bone marrow granulocyte macrophage colony-forming units (CFU-GM) remained unchanged. The Lewis lung carcinoma was used to assess the response of both the primary tumor and metastatic lung disease to treatment with minocycline (14 x 5 mg/kg) given alone or in combination with several cytotoxic anticancer drugs or with radiation delivered locally to the primary tumor. Of the various therapies tested, minocycline proved to be especially effective as an addition to treatment with cyclophosphamide both in increasing the response of the primary tumor and in reducing the number of lung metastases. The tumor growth delay produced by melphalan, radiation, Adriamycin, and bleomycin was also increased by the addition of minocycline to these therapies. These results indicate that minocycline given in clinically achievable doses may be an effective addition to some standard therapeutic regimens and that the mechanism of modulation by minocycline is likely to involve an effect of the drug on the host and not its direct interaction with other therapeutic modalities at the level of the tumor cell.

Animals↗
PubMed1992

Effect of a bovine hemoglobin preparation on the response of the FSaIIC fibrosarcoma to chemotherapeutic alkylating agents.

Polymerized bovine hemoglobin solutions (PBHS) are being actively investigated as blood substitutes. In studies analogous to those we conducted with perfluorochemical emulsions/carbogen, we have examined the effect of PBHS +/- carbogen (95% O2, 5% CO2) breathing on the antitumor efficacy of melphalan, cyclophosphamide, N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) and cis-diamminedichloroplatinum(II) (cis-platin). The tumor growth delay of the FSaIIC fibrosarcoma treated with melphalan (10 mg/kg), cyclophosphamide (150 mg/kg), cisplatin (10 mg/kg) and BCNU (15 mg/kg) was increased about 2.2-fold, about 2.1-fold, about 1.2-fold and about 1.5-fold, respectively, when PBHS (12 mg/kg) was administered i.v. before each drug was injected i.p. The tumor growth delay produced by each drug was further increased when carbogen breathing for 6 h was allowed after administration of the drug and PBHS. In tumor cell survival experiments 24 h following drug treatment, the addition of PBHS increased the tumor cell killing of both melphalan and cyclophosphamide by about a factor of 10 at the lowest doses of each drug tested (10 mg/kg for melphalan and 100 mg/kg for cyclophosphamide) compared to the drug alone. However, at higher drug doses this effect was lost. The toxicity of each antitumor agent toward bone marrow (granulocyte/macrophage-colony-forming units) was increased 2- to 3-fold by the combined treatment. These results suggest that use of PBHS +/- carbogen breathing may add significantly to the efficacy of antitumor alkylating agents, however, the in vivo/in vitro data suggest that there will be increased bone marrow toxicity with this approach. This needs to be taken into account in the design of clinical trials.

Alkylating Agents↗
PubMed1992

A new concentrated perfluorochemical emulsion and carbogen breathing as an adjuvant to treatment with antitumor alkylating agents.

Many anticancer drugs require oxygen to be cytotoxic or are selectively cytotoxic toward cells under oxygenated conditions. The effects of the dilute perfluorochemical emuolsion Fluosol with a wide variety of chemotherapeutic agents have been explored; however, it has not been possible to determine the optimal level of circulating perfluorochemical emulsion with anticancer drugs because the volume of Fluosol that may be administered is limiting. Using a new concentrated perfluorochemical emulsion, a wide range of perfluorochemical doses has been examined in combination with melphalan, cyclophosphamide and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in the FSaIIC fibrosarcoma. When the perfluorochemical emulsion was administered by injection i.v. just prior to the injection of melphalan (10 mg/kg), cyclophosphamide (150 mg/kg) or BCNU (50 mg/kg), the greatest tumor growth delays were obtained with dosage levels between 4 g and 12 g of the perfluorochemical perfluorooctyl bromide/kg. With each drug the greatest tumor growth delays were obtained when the drug was prepared in the emulsion and the combination injected i.v. In each case, each dose of drug was followed by 6 h of breathing carbogen. The addition of the perfluorochemical emulsion/carbogen breathing to treatment with melphalan, BCNU or cyclophosphamide resulted in significant increases in the killing of tumor cells by these drugs without a concomitant increase in toxicity to bone marrow granulocyte/macrophage-colony-forming units. In each case, preparing the drug in the perfluorochemical emulsion was most effective. These results indicate that clinical trial of this perfluorochemical emulsion/carbogen breathing in combination with cancer chemotherapy may be warranted.

Administration, Inhalation↗
PubMed1992

Interaction of D,L- and D-tetraplatin with hyperthermia in vitro and in vivo.

The cytotoxicities of D,L-tetraplatin and D-tetraplatin were evaluated at 37 degrees C, 42 degrees C and 43 degrees C at normal pH, at pH 6.45 and under normally oxygenated and hypoxic conditions in EMT-6 cells in vitro. The D-isomer was also tested in FSaIIC cells in vitro. Under these various conditions the pure D-isomer was very similar in cytotoxicity with the racemic mixture. Like cisplatin, both D,L- and D-tetraplatin were selectively cytotoxic toward normally oxygenated cells under acidic pH (6.45) conditions at 37 degrees C. In both cell lines the cytotoxicity of D,L- and D-tetraplatin was markedly increased at hyperthermic temperatures. Under the same conditions platinum levels in EMT-6 cells exposed to D,L- or D-tetraplatin were higher than in cells exposed to cisplatin, and unlike cisplatin there was an increase in intracellular platinum levels when the cells were exposed to D,L- or D-tetraplatin at 42 degrees C compared with 37 degrees C. The tumour growth delay of the FSaIIC fibrosarcoma was the same for D,L- and D-tetraplatin. A dose of 10 mg/kg intraperitoneally of tetraplatin produced a tumour growth delay of about 4.3 days which was increased to about 6 days with the addition of local hyperthermia (43 degrees C, 30 min) to the drug treatment. The tumour cell survival assay also showed no difference between D,L- and D-tetraplatin and a log-linear increase in tumour cell killing with increasing drug dose which was increased 1.5-3-fold with local hyperthermia. D,L- and D-tetraplatin were relatively much more cytotoxic toward bone marrow colony forming units of granulocyte-macrophage progenitors (CFU-GM) than was cisplatin and this cytotoxicity was increased about 5-10-fold under hyperthermic conditions. There was an increase in DNA crosslink formation in tumours when hyperthermia accompanied tetraplatin treatment. Overall, D,L- and D-tetraplatin produced very similar responses under hyperthermic conditions in both tumour and normal tissues, and may be a useful agent in combination with local hyperthermia.

Animals↗
PubMed1992

Multiple modality treatment of carcinoma cells with Pt(Rh-123)2 plus x-ray plus light.

A complex of platinum tetrachloride with two molecules of rhodamine-123 (Rh-123), Pt(Rh-123)2, has been reported to act as hypoxic cell radiosensitizer of carcinoma cells in vitro and in vivo. In the present paper we report that Pt(Rh-123)2 photosensitizes human mammary carcinoma (MCF-7) cells and cis-platinum resistant human mammary carcinoma (MCF-7/CP) cells to 400-800 nm light in vitro. The efficiency of photosensitization by Pt(Rh-123)2 was 10 times greater than for Rh-123. Combination therapy using Pt(Rh-123)2 plus x-ray plus light was also much more effective compared to the combination therapy using Rh-123 plus x-ray plus light. After 15 microM of Rh-123 plus x-ray (0-8 Gy) plus light (5 J/cm2) treatment, cell survival curve was parallel to the x-ray cell survival curve with an initial decrease in the surviving fraction corresponding to the drug plus light mediated killing. Cell killing caused by Rh-123 (15 microM) plus x-ray (0-8 Gy) plus light (5 J/cm2) was additive as determined by the product of the surviving fraction after Rh-123 plus light and x-ray. In contrast, for 15 microM of Pt(Rh-123)2 plus x-ray (8 Gy) plus light (5 J/cm2) treatment, whereas additive killing predicts a survival fraction of approximately 0.024, in reality, the combination therapy caused the survival fraction to decrease to 0.0012, implying that the cell killing was enhanced by a factor of 20. Using Pt(Rh-123)2 plus x-ray plus light, supra-additive cell killing was also observed under hypoxic conditions, although compared to normally oxygenated conditions the degree of cytotoxicity was significantly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1992

Effect of a bovine hemoglobin preparation (SBHS) on the response of two murine solid tumors to radiation therapy or chemotherapeutic alkylating agents.

When tested in mice bearing the Lewis lung tumor with 2, 3, or 4 Gy daily for 5 days, SBHS produced a dose-modifying factor of 1.6 that was increased to 2.1 with carbogen. The addition of SBHS (1.32 gm protein/kg) to treatment with melphalan (MEL) resulted in a 2.2-fold increase in the tumor growth delay (TGD). The combination of SBHS with carbogen (6 h) produced a 3.6-fold increase in TGD compared with MEL alone. The addition of SBHS to treatment with cyclophosphamide (CTX) resulted in a 2-fold increase in the TGD. However, the combination of SBHS and carbogen was much more effective resulting in a 4.6-fold increase in TGD. There was a 1.3-fold increase in TGD with SBHS and CDDP compared with CDDP alone. The combination of SBHS and carbogen was a more effective addition to CDDP resulting in a 1.9-fold increase in TGD. The addition of SBHS to treatment with BCNU increased the TGD produced by BCNU by 1.5-fold. The combination of SBHS/BCNU and carbogen resulted in a 2.3-fold increase in TGD over that obtained with BCNU alone.

Alkylating Agents↗
PubMed1992

Enhancement by perflusion emulsion (Oxygent) and carbogen breathing of the tumor growth delay of the FSaIIC fibrosarcoma after treatment with antitumor alkylating agents.

Many anticancer drugs require oxygen to be cytotoxic, or are selectively cytotoxic toward cells under oxygenated conditions. The effects of the dilute perfluorochemical emulsion Fluosol-DA with a wide variety of chemotherapeutic agents have been explored; however, it has not been possible to determine the optimal level of circulating perfluorochemical emulsion with anticancer drugs because the volume of Fluosol that may be administered in limited. Using a concentrated 90% Perflubron emulsion, Oxygent, a wide range of perfluorochemical emulsion doses have been examined in combination with melphalan, cyclophosphamide and BCNU in a murine solid tumor model. When Oxygent was administered by injection i.v. just prior to the injection of melphalan (10 mg/kg), the greatest tumor growth delays were obtained with Oxygent levels between 4 and 12 g PFC/kg. With each of these drugs the greatest tumor growth delays were obtained when the drug was prepared in the emulsion and the combination injected i.v. In each case, each dose of drug was followed by 6 h. of breathing carbogen.

Alkylating Agents↗
PubMed1992

Enhancement of fractionated radiation therapy by an experimental concentrated perflubron emulsion (Oxygent) in the Lewis lung carcinoma.

The concentrated Perflubron emulsion, Oxygent, in combination with breathing a 95% oxygen atmosphere, significantly enhanced the response of the murine Lewis lung carcinoma to fractionated radiation therapy. Administration of 4 to 12 g PFC/kg was most effective if administered prior to each x-ray fraction, however, alternated day and even once weekly administration of 8 or 12 PFC/kg and 95% oxygen breathing with each x-ray fraction resulted in significant improvements in tumor growth delay.

Animals↗
PubMed1991

Combination of the minor groove-binder U73-975 or the intercalator mitoxantrone with antitumor alkylating agents in MCF-7 or MCF-7/CP cells.

In an effort to improve the cytotoxicity of clinically used anticancer alkylating agents, the topoisomerase II inhibitory drugs U73-975 or mitoxantrone were added to cell cultures exposed to CDDP, carboplatin, BCNU, melphalan or thiotepa. In the MCF-7 human breast cancer cell line and in the MCF-7/CP (CDDP resistant) subline, U73-975 and mitoxantrone were both potent cytotoxic agents (IC50 0.002 microM and 0.006 microM for U73-975, respectively and 0.8 microM and 0.1 microM for mitoxantrone, respectively). As evaluated by isobologram analysis, the addition of either U73-975 or mitoxantrone to 1 h exposure to CDDP resulted in greater-than-additive killing in the MCF-7 parent cells. While U73-975 was also greater-than-additive in cytotoxicity with CDDP in the MCF-7/CP line, mitoxantrone and CDDP were only additive in cytotoxicity in these cells. In the case of carboplatin, the addition of U73-975 or mitoxantrone to treatment with the drug resulted in greater-than-additive cell killing in the MCF-7 parental cell line but in the MCF-7/CP cell line these combinations were only additive in cell killing. Addition of U73-975 to treatment with BCNU resulted in only additive cytotoxicity in both cell lines; however, the combination of mitoxantrone with BCNU resulted in greater-than-additive cell killing in both the parental and CDDP resistant cell lines. When either U73-975 or mitoxantrone was added to treatment with melphalan greater-than-additive cytotoxicity resulted in both cell lines except at low melphalan concentrations in the MCF-7/CP cell line. Finally, the addition of either modulator to treatment with thiotepa in the MCF-7 cell line produced variable interactions depending on thiotepa concentration, but in the MCF-7/CP cell line either modulator in combination with thiotepa caused greater-than-additive cell killing. These results indicate that the addition of topoisomerase II inhibitory drugs may substantially increase the cytotoxicity of some alkylating agents. In vivo experiments are necessary, however, to ascertain whether a therapeutic gain is achievable.

Adenocarcinoma↗