Biomedical subjects

S A Holden

Publications and source records attributed to S A Holden.

At least 19 recordsLinked to original sources

PubMed2001

Augmentation of antitumor activity of an antibody-interleukin 2 immunocytokine with chemotherapeutic agents.

PURPOSE: Immune-based therapies, such as the immunocytokine huKS-IL2, exert potent antitumor responses in some animal models by targeting cytokine activity to the tumor microenvironment. We found that certain chemotherapy agents in the appropriate dose and schedule can augment the antitumor activity of huKS-IL2. EXPERIMENTAL DESIGN: Chemotherapy agents were given in a single dose followed 1 day (paclitaxel) or 3 days (cyclophosphamide) later with five daily doses of huKS-IL2 in mice bearing established s.c. tumors, liver metastases, or lung metastases. Tumor models used were CT26/KSA colon, 4T1/KSA mammary, or LLCKSA Lewis lung carcinomas. To measure huKS-IL2 distribution, radiolabeled protein was given to CT26/KSA tumor-bearing mice 1 or 24 h after paclitaxel. huKS-IL2 levels in the tumors were evaluated. RESULTS: Both paclitaxel and cyclophosphamide followed by huKS-IL2 resulted in enhanced antitumor responses compared with either of the treatments alone in the three different tumor models. Results from studies to determine whether the role of the cytotoxic agents in antitumor activity enhancement was related to tumor uptake indicated that a larger fraction of the radiolabeled huKS-IL2 penetrated the tumors when it was administered 24 h after cytotoxic drug "sensitization." CONCLUSION: These data support the idea that prior drug therapy serves to decompress the tumor and lower the diffusion barrier for macromolecules, thus allowing for increased uptake of the huKS-IL2 immunocytokine into the tumor microenvironment. Because the toxicity of the immunocytokine is relatively low at optimal doses, the therapeutic index would likely be greater with the combination treatments.

Animals↗

PubMed1998

Differentiation and reversal of malignant changes in colon cancer through PPARgamma.

PPARgamma is a nuclear receptor that has a dominant regulatory role in differentiation of cells of the adipose lineage, and has recently been shown to be expressed in the colon. We show here that PPARgamma is expressed at high levels in both well- and poorly-differentiated adenocarcinomas, in normal colonic mucosa and in human colon cancer cell lines. Ligand activation of this receptor in colon cancer cells causes a considerable reduction in linear and clonogenic growth, increased expression of carcinoembryonic antigen and the reversal of many gene expression events specifically associated with colon cancer. Transplantable tumors derived from human colon cancer cells show a significant reduction of growth when mice are treated with troglitazone, a PPARgamma ligand. These results indicate that the growth and differentiation of colon cancer cells can be modulated through PPARgamma.

Adenocarcinoma↗

PubMed1997

Host distribution and response to antitumor alkylating agents of EMT-6 tumor cells from subcutaneous tumor implants.

PURPOSE: Minimal residual tumor or minimal residual metastatic disease is a major clinical problem for detection and treatment. The purpose of the study was to develop a model system to detect the occurrence and response to therapy of minimal residual tumor in distant organs. METHODS: Animals bearing subcutaneously growing established (day 8) murine EMT-6 mammary carcinoma tumors were treated with single doses of the antitumor alkylating agents, cyclophosphamide, melphalan, cis-diamminedichloroplatinum(II) (CDDP) or thiotepa. Tumors, livers, lungs, brain, spleen, blood and bone marrow were collected from the animals 24 h later and single-cell suspensions of these tissues were plated and cultured under conditions suitable for tumor cell colony growth. RESULTS: Tumor cell colonies grew from each of the tissues with varying frequency ranging from about 6 x 10(3) tumor cell colonies per 10(6) cells plated from the liver, to about 2 tumor cell colonies per 10(6) cells plated from the brain. There was a wide range of sensitivity, spanning 2- to 3-log of the tumor cells, to the antitumor alkylating agents depending upon the tissue in which the tumor cells were located. Tumor cells in the circulating blood were most sensitive to the antitumor alkylating agents with no colony growth after treatment of the animals with any of the four drugs tested. The primary tumor growing subcutaneously in the upper hindleg of the animals was also relatively sensitive to each of the four antitumor alkylating agents tested. EMT-6 tumor cells in the spleen were very sensitive to cyclophosphamide, moderately sensitive to melphalan, less sensitive to CDDP and least sensitive to thiotepa. EMT-6 tumor cells in the bone marrow were moderately sensitive to cyclophosphamide, melphalan and thiotepa but less sensitive to CDDP. EMT-6 tumor cells in the lungs were relatively sensitive to thiotepa, moderately sensitive to cyclophosphamide and CDDP and least sensitive to melphalan. EMT-6 tumor cells in the liver or brain were least responsive to treatment of the host with any of the four antitumor alkylating agents tested. CONCLUSIONS: Treatment of the tumor-bearing animals with the antiangiogenic combination, TNP-470/minocycline, markedly increased EMT-6 tumor cell killing by cyclophosphamide in the liver, lungs and bone marrow. These results indicate that location within the host is an important determinant in the response of tumor cells to therapy.

Animals↗

PubMed1996

Transforming growth factor-beta in in vivo resistance.

The potential role of transforming growth factor-beta in in vivo resistance was examined by administration of transforming growth factor-beta-neutralizing antibodies to animals bearing the EMT-6/Parent tumor or the antitumor alkylating resistance tumors, EMT-6/CTX or EMT-6/CDDP. Treatment of tumor bearing animals with anti-TGF-beta antibodies by intraperitoneal injection daily on days 0-8 post-tumor cell implantation increased the sensitivity of the EMT-6/Parent tumor to cyclophosphamide (CTX) and cisplatin (CDDP) and markedly increased the sensitivity of the EMT-6/CTX tumor to CTX and the EMT6/CDDP tumor to CDDP, as determined by tumor cell survival assay. Bone marrow granulocyte-macrophage colony-forming units (CFU-GM) survival was determined from these same animals. The increase in the sensitivity in the tumors upon treatment with the anti-TGF-beta antibodies was also observed in increased sensitivity of the bone marrow CFU-GM to CTX and CDDP. Treatment of non-tumor-bearing animals with the anti-TGF-beta regimen did not alter blood ATP or serum glucose level but did decrease serum lactate levels. This treatment also decreased hepatic glutathione, glutathione S-transferase, glutathione reductase, and glutathione peroxidase in non-tumor bearing animals by 40-60% but increased hepatic cytochrome P450 reductase in these normal animals. Animals bearing the EMT-6/CTX and EMT-6/CDDP tumors had higher serum lactate levels than normal or EMT-6/Parent tumor-bearing animals; these were decreased by the anti-TGF-beta regimen. Treatment of animals bearing any of the three tumors with the anti-TGF-beta regimen decreased by 30-50% the activity of hepatic glutathione S-transferase and glutathione peroxidase, and increased by 35-80% the activity of hepatic cytochrome P450 reductase. In conclusion, treatment with transforming growth factor-beta-neutralizing antibodies restored drug sensitivity in the alkylating agent-resistant tumors, altering both the tumor and host metabolic states.

Animals↗

PubMed1996

Comparison of several antiangiogenic regimens alone and with cytotoxic therapies in the Lewis lung carcinoma.

The efficacy of several potential antiangiogenic agents, TNP-470, minocycline, suramin, genistein, interferon delta 4, 14(sulfated)-beta-cyclodextrin and tetrahydrocortisol, alone and in combination with cytotoxic therapies was examined against primary and metastatic Lewis lung carcinoma. The antiangiogenic agents when administered as single agents or in two-agent combinations were only modestly active as antitumor agents. Three antiangiogenic agent combinations, TNP-470/minocycline, TNP-470/14(SO4)beta-CD/THC and minocycline/14(SO4)beta-CD/THC, produced significant increases in tumor growth delay and decreases in the number of lung metastases when administered along with cyclophosphamide compared with cyclophosphamide alone. Two antiangiogenic agent combinations, minocycline/interferon delta 4 and minocycline/14(SO4)beta-CD/THC, produced significant decreases in the number of lung metastases when administered alone with adriamycin compared with adriamycin alone. The antiangiogenic combinations of TNP-470/minocycline, TNP-470/suramin, TNP-470/genistein, TNP-470/interferon delta 4 and TNP-470/l4(SO4)beta-CD/THC, resulted in increased tumor growth delays when administered along with CDDP, BCNU, fractionated radiation or 5-fluorouracil. There was not always a direct correlation between the antiangiogenic regimen that was most beneficial against the primary tumor as compared with disease metastatic to the lungs. These studies establish that a broad range of antiangilogenic therapies can interact in a positive manner with cytotoxic therapies.

Animals↗

PubMed1996

Antitumor efficacy and pharmacokinetic analysis of 4-hydroperoxycyclophosphamide in comparison with cyclophosphamide +/- hepatic enzyme effectors.

4-Hydroperoxycyclophosphamide is an oxazaphosphorine which is readily converted without enzymatic involvement to 4-hydroxycyclophosphamide-a key intermediate in the antitumor activity of this class of drugs. The efficacy of 4-hydroperoxycyclophosphamide as a systemically administered antitumor drug was examined in mice bearing EMT-6 mammary carcinoma and in rats bearing 13762 mammary carcinoma in comparison with other oxazaphosphorines. 4-Hydroperoxycyclophosphamide was a more potent tumor cell killing agent than cyclophosphamide or ifosfamide in animals bearing the EMT-6 tumor. There were no significant differences in the toxicity to bone marrow amongst the three oxazaphosphorines. 4-Hydroperoxycyclophosphamide (90 mg/kg) on days 7, 9 and 11 produced 11.5 days of tumor growth delay compared with 10.4 days and 7.1 days for cyclophosphamide (150 mg/kg) and ifosfamide (150 mg/kg) administered on the same schedule, respectively. 4-Hydroperoxycyclophosphamide was tolerated at 90 mg/kg daily for 5 days and at 75 mg/kg twice daily for 4 days producing tumor growth delays of 14.4 days and 16.6 days, respectively. In rats bearing 13762 tumors, 4-hydroperoxycyclophosphamide (90 mg/kg) on days 8, 10 and 12 produced a tumor growth delay of 14.5 days compared with 8.9 days for cyclophosphamide (100 mg/kg) administered on the same schedule. Treatment of 13762 tumor-bearing rats with phenobarbital, pentobarbital or etanidazole increased the tumor growth delay produced by cyclophosphamide while treatment with cimetidine decreased the tumor growth delay produced by cyclophosphamide but not significantly. Administration of 4-hydroperoxycyclophosphamide (90 mg/kg) produced blood concentrations of 4-hydroxycyclophosphamide three-fold higher than those produced by administration of cyclophosphamide (100 mg/kg) at 15 min after drug injection. Treatment with phenobarbital or pentobarbital increased 4-hydroxycyclophosphamide blood concentration while pretreatment with cimetidine decreased 4-hydroxycyclophosphamide blood concentration from cyclophosphamide. 4-Hydroperoxycyclophosphamide is an effective antitumor agent worthy of further investigation.

Adenocarcinoma↗

PubMed1995

Influence of an anti-angiogenic treatment on 9L gliosarcoma: oxygenation and response to cytotoxic therapy.

Tissue oxygen tensions were measured in subcutaneously growing rat 9L gliosarcoma under normal air and carbogen breathing conditions prior to and after i.v. administration of a perflubron emulsion. When these animals were treated with the anti-angiogenic agents TNP-470 and minocycline for 5 days prior to oxygen measurement, tumor hypoxia was decreased compared with untreated tumors. Hypoxia, defined as the percent of pO2 readings < or = 5 mm Hg, was decreased from 71% in untreated air-breathing controls to 34% in animals treated with the anti-angiogenic agents, the perflubron emulsion and carbogen breathing. These effects were manifest in the increased response of the tumor to single-dose (10, 20 and 30 Gy) radiation therapy. Twenty-four hours after treatment with BCNU oxygenation of the tumors was not altered; however, 24 hr after administration of adriamycin oxygenation of the tumors was increased such that hypoxia in adriamycin-treated tumors in animals receiving the perflubron emulsion and carbogen was reduced to 21%. Tumor growth delay in the s.c. tumors was increased by the addition of treatment with the anti-angiogenic agents from day 4 through day 18 post-tumor cell implantation along with BCNU or adriamycin on days 7-11. Administration of the perflubron emulsion and carbogen breathing resulted in increased tumor growth delay with the chemotherapeutic agents alone and in combination with the anti-angiogenic agents. Life span in animals bearing intracranially implanted 9L gliosarcoma progressively increased with administration of the anti-angiogenic agents and then the anti-angiogenic agents and perflubron emulsion/carbogen compared to treatment with BCNU or adriamycin.

Animals↗

PubMed1995

Potentiation of cytotoxic therapies by TNP-470 and minocycline in mice bearing EMT-6 mammary carcinoma.

The ability of the antiangiogenic agents TNP-470 and minocycline, singly or in combination, to potentiate the antitumor effects of several cytotoxic therapies was assessed in the murine EMT-6 mammary carcinoma as well as in two drug resistant sublines of that tumor designated EMT-6/CTX and EMT-6/CDDP. The antiangiogenic agents alone or in combination did not alter the growth of the tumors. However, their administration along with cyclophosphamide, CDDP, or thiotepa substantially increased the tumor growth delay produced by these cytotoxic therapies in tumors responsive to the drugs--the increase was about 2-fold for TNP-470 and minocycline together. In drug resistant tumors, treatment with the antiangiogenic agents did not reverse drug resistance but did increase the effect of the cytotoxic drugs. Treatment with TNP-470/minocycline also increased the oxygenation of each of the three tumors. Thus, TNP-470/minocycline administration increased the efficacy of fractionated radiation therapy, especially when used along with a perflubron emulsion oxygen delivery agent/carbogen. These results indicate that treatment regimens including therapies directed toward the proliferating normal cells within a tumor mass as well as therapies directed toward the malignant cells can produce improved outcomes.

Animals↗

PubMed1995

A preclinical model for sequential high-dose chemotherapy.

Dose-intensive chemotherapy regimens have entered clinical trial based on the notion that log-linear tumor-cell killing, especially with antitumor alkylating agents, is maintained at higher drug doses. Several clinical trials employing two intensifications are underway. Using the tumor-cell survival assay, animals bearing the FSaII fibrosarcoma were treated with single doses of various chemotherapeutic agents once or twice with a 3- or 7-day interval between the drugs. Isobologram methodology was used to determine if the sequential treatment regimens resulted in subadditive, additive or greater-than-additive tumor-cell killing. When melphalan was followed 3 or 7 days later by a second dose of melphalan there was evidence of resistance to the second dose of melphalan as indicated by subadditive tumor-cell killing. Melphalan followed 3 days later by cyclophosphamide (300 mg/kg) produced greater-than-additive tumor-cell killing, however, when the interval was 7 days the resulting tumor-cell killing was subadditive. Melphalan followed 3 or 7 days later by thiotepa or carboplatin produced subadditive-to-additive tumor-cell killing. Adriamycin followed 3 days later by melphalan, cyclophosphamide, thiotepa, or carboplatin resulted in subadditive-to-additive tumor-cell killing by the combinations. These results indicate that sequential drug-intensive treatments may not optimize tumor-cell killing in vivo.

Animals↗

PubMed1995

Cytotoxicity of antitumor platinum complexes with L-buthionine-(R,S)-sulfoximine and/or etanidazole in human carcinoma cell lines sensitive and resistant to cisplatin.

Human 2008 ovarian carcinoma cells and the C13 CDDP-resistant subline and human MCF-7 breast carcinoma cells and the MCF-7/CDDP CDDP-resistant subline were exposed to L-buthionine-(S,R)-sulfoximine (50 microM) for 48 h prior to and during exposure for 1 h to the antitumor platinum complexes, cis-diamminedichloroplatinum(II), carboplatin or D,L-tetraplatin and/or to etanidazole (1 mM) for 2 h prior to and during exposure for 1 to the antitumor platinum complexes. These modulators alone did not significantly alter the cytotoxicity of CDDP toward either parental line. A twofold enhancement in cytotoxicity was observed with carboplatin in the 2008 cells and with D,L-tetraplatin in both parental lines with the single modulators. The modulator combination (buthionine sulfoximine/etanidazole) was very effective along with D,L-tetraplatin in both the MCF-7 parent and MCF-7/CDDP cell lines where at the higher platinum complex concentrations there was 1.5 to 3 logs increased killing of cells by the drug plus the modulators compared with the drug alone. Similarly, when C13 cells were exposed to CDDP (100 microM) or D,L-tetraplatin (100 microM) along with buthionine sulfoximine and etanidazole there was a 2-log increase in cell killing compared with exposure to the platinum complex alone. Treatment of each of the four cell lines with buthionine sulfoximine decreased both the non-protein and total sulfhydryl content of the cells. Treatment with the combination of modulators did not produce a further decrease in cellular sulfhydryl content compared with buthionine sulfoximine alone. The total sulfhydryl content in MCF-7 cells and 2008 cells exposed to buthionine sulfoximine and etanidazole was 58% and 31% of normal and the total sulfhydryl content of MCF-7/CDDP cells and C13 cells treated the same way was 54% and 23% of normal, respectively. DNA alkaline elution was used to assess the impact of exposure to the modulators, buthionine sulfoximine and etanidazole, alone and in combination on the cross linking of DNA by the antitumor platinum complexes in the MCF-7 and MCF-7/CDDP cell lines. Overall, the increases in DNA cross linking factors were greater in the MCF-7 cells than in the MCF-7/CDDP cells. These results indicate a possible clinical potential for this modulator combination.

Antimetabolites, Antineoplastic↗

PubMed1995

Antifolates can potentiate topoisomerase II inhibitors in vitro and in vivo.

Antifolates have been shown to increase the DNA strand breaks produced by the topoisomerase inhibitor etoposide. PT523 is a potent new antifolate that cannot be polyglutamated. Human SCC-25 squamous carcinoma cells were exposed to methotrexate, trimetrexate or PT523 at a concentration of 5 microM for 24 h along with various concentrations of etoposide or novobiocin during the final 2 h. Isobologram analysis of the treatment combinations indicated that exposure of the cells to PT523/etoposide, methotrexate/etoposide, PT523/novobiocin, methotrexate/novobiocin and trimetrexate/novobiocin resulted in greater than additive cytotoxicity. DNA alkaline elution studies with the same drug combinations indicated that there were three- to four-fold increases in the radiation equivalent (rad equivalent) strand breaks in the cellular DNA with etoposide or novobiocin along with the antifolate compared with the topoisomerase II inhibitors alone. Tumor growth delay studies were carried out in the murine SCC VII squamous carcinoma. PT523 (0.5 mg/kg) and methotrexate (2 mg/kg) were administered by 7-day continuous infusion while trimetrexate (3.75 mg/kg) was administered intraperitoneally daily on days 7-9. Etoposide (10 mg/kg) and novobiocin (100 mg/kg) were administered intraperitoneally on alternate days (7, 9, 11). The combinations of PT523 with etoposide or novobiocin were significantly more effective than methotrexate and etoposide or novobiocin, producing tumor growth delays of 8.4 days and 6.9 days, respectively. Overall, the antifolate/topoisomerase II inhibitor treatment combinations produced tumor growth delays that were apparently additive to greater than additive.

Animals↗

PubMed1994

Long-term persistence and cytokinetics of human tumor cells in vitro following high-dose alkylating agent exposure.

Relapse after high-dose alkylating agent therapy continues to be an important clinical issue. To begin to understand the characteristics of cells surviving alkylating agent exposure human MCF-7 breast carcinoma cells were exposed to a range of concentrations of melphalan or cis-diamminedichloroplatinum(II) and cell survival determined by colony formation over a time course of 4 weeks. When antitumor alkylating agent exposure killed 3-4 logs of cells as determined by surviving fraction after 1 week of colony formation a progressive increase in surviving fraction was evident over the 4-week course of the experiment. Many attached single cells with abnormal morphology were evident in these dishes; however, the colonies which arose over the 4-week observation time were made up of cells morphologically indistinguishable from the control cells. Cell cycle patterns in the cultures exposed to high concentrations of the antitumor alkylating agents indicated a block in G2/M but by 4 weeks post-drug exposure most had returned to a normal exponential growth pattern. When MCF-7 cells or human SW2 small cell lung cancer cells were exposed to a concentration of melphalan or cis-diamminedichloroplatinum(II) that killed 1-2 logs of cells followed by exposure to a concentration range of the same drug for 24 h or 7 days later resistance to the second drug exposure was evident in both cell lines. Using [14C]melphalan the uptake of the drug into MCF-7 cells pre-treated was compared. Decreased drug uptake did not appear to be a factor in resistance to melphalan observed upon re-exposure to the drug. The potential clinical implications of these findings is discussed.

Breast Neoplasms↗

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↗

PubMed1994

Potentiation of cytotoxic cancer therapies by TNP-470 alone and with other anti-angiogenic agents.

The ability of TNP-470, a synthetic analog of fumagillin which has been described as an anti-angiogenic agent, to potentiate cytotoxic cancer therapies was investigated in vivo in the murine FSaIIC fibrosarcoma and the Lewis lung carcinoma. TNP-470 was more toxic toward FSaIIC tumor cells from tumors treated in vivo than toward bone-marrow CFU-GM from the same animals. TNP-470 had a dose-modifying effect on the toxicity of cyclophosphamide toward FSaIIC tumor cells which amounted to an 8-fold increase in tumor-cell killing at a cyclophosphamide dose of 500 mg/kg. Treatment with TNP-470 and minocycline increased the permeability of the FSaII fibrosarcoma in vivo to the fluorescent dye Hoechst 33342 and increased the killing of both the bright and the dim tumor cells by cyclophosphamide. TNP-470, especially in combination with minocycline, formed a highly effective modulator combination for treatment of the Lewis lung carcinoma with cytotoxic cancer therapies against primary and metastatic disease. The combination of TNP-470/minocycline and cyclophosphamide led to 40 to 50% long-term survivors in Lewis-lung-carcinoma-bearing animals. Our results indicate that the use of anti-angiogenic modulators in cancer therapy is a very promising area for further study.

Animals↗

PubMed1994

In vivo modulation of several anticancer agents by beta-carotene.

The ability of the collagenase inhibitor minocycline and of beta-carotene to act as positive modulators of cytotoxic anticancer agents was assessed in vitro and in vivo. Cell-culture studies were conducted using the human SCC-25 squamous carcinoma cell line. Simultaneous exposure of the cells to minocycline and beta-carotene or 13-cis-retinoic acid along with cisplatin (CDDP) resulted in a small decrease in the cytotoxicity of the CDDP. The addition of each of the modulator combinations for 1 h or 24 h to treatment with melphalan (L-PAM) or carmustine (BCNU) resulted in greater-than-additive cytotoxicity with each of four regimens. The modulator combinations of minocycline and beta-carotene applied for 1 h or 24 h and the modulator combination of minocycline and 13-cis-retinoic acid produced greater-than-additive cytotoxicity at 50 microM 4-hydroperoxycyclophosphamide (4-HC), whereas minocycline and 13-cis-retinoic acid applied for 1 h was antagonistic with 4-HC and the other modulator treatments at low concentrations of 4-HC resulted in subadditive cytotoxicity. The effect of treatment with beta-carotene alone and in combination with several different anticancer agents was examined in two murine solid tumors, the FSaII fibrosarcoma and the SCC VII carcinoma. Administration of the modulators alone or in combination did not alter the growth of either tumor. Whereas increases in tumor growth delay occurred with the antitumor alkylating agents and beta-carotene and with minocycline and beta-carotene, a diminution in tumor growth delay was produced by 5-fluorouracil in the presence of these modulators. The modulator combination also resulted in increased tumor growth delay with adriamycin and etoposide. Tumor-cell survival assay showed increased killing of FSaII tumor cells with the modulator combination and melphalan or cyclophosphamide as compared with the drugs alone. These results indicate that further investigation of this modulator strategy is warranted.

Animals↗

PubMed1994

CAI: effects on cytotoxic therapies in vitro and in vivo.

CAI (NSC 609974; L651582), a new agent that has demonstrated antimetastatic activity in vitro and in vivo, was not very cytotoxic toward EMT-6 mouse mammary carcinoma cells in culture or toward FSaIIC fibrosarcoma cells in vivo. Coexposure of EMT-6 cells to CAI and antitumor alkylating agents under various environmental conditions did not markedly increase the cytotoxicity of cisplatin (CDDP), melphalan, or carmustine (BCNU). However, the combination of CAI and 4-hydroperoxycyclophosphamide (4-HC) produced much greater than additive killing of EMT-6 cells. CAI also increased the sensitivity of hypoxic EMT-6 cells to X-rays. CAI increased the cytotoxicity of cyclophosphamide toward FSaIIC tumor cells when animals were treated with single doses of both drugs. The effect of CAI on tumor cell killing by cyclophosphamide was greatest at high doses of the antitumor alkylating agent. CAI administration appeared to result in increased serum levels of prostaglandin E2 and leukotriene B4 in animals bearing the Lewis lung tumor. Administration of CAI on days 4-18 did not alter the growth of the Lewis lung carcinoma but did result in an increase in the tumor-growth delay produced by treatment with CDDP, cyclophosphamide, melphalan, BCNU, and fractionated radiation. Although CAI did not reduce the number of lung metastases present in Lewis lung carcinoma-bearing mice on day 20, it did appear to reduce the number of large (vascularized) metastases present on that day.

Aminoimidazole Carboxamide↗

PubMed1994

Cyclooxygenase and lipoxygenase inhibitors as modulators of cancer therapies.

Like many clinical non-small-cell lung cancers, the Lewis lung carcinoma produces prostaglandins. The Lewis lung carcinoma was used as a model of both primary and metastatic disease to assess the ability of cyclooxygenase inhibitors (mefenamic acid, diflunisal, sulindac, and indomethacin), the collagenase inhibitor minocycline, and the lipoxygenase inhibitor phenidone to act as modulators of cytotoxic cancer therapies. Although none of the single modulators given i.p. daily on days 4-18 altered tumor growth or the number of metastases found on day 20, modulator combinations consisting of minocycline/a cyclooxygenase inhibitor and, especially, of phenidone/a cyclooxygenase inhibitor resulted in modest tumor growth delay and a decreased number of lung metastases on day 20. The most effective modulators of cisplatin (CDDP) were phenidone/sulindac and phenidone/indomethacin, which led to 2.4- to 2.5-fold increases in the tumor growth delay produced by CDDP. The most effective modulations of cyclophosphamide resulted from administration of minocycline, minocycline/sulindac, or phenidone/sulindac and led to 2.0- to 2.1-fold increases in tumor growth delay by cyclophosphamide. The most effective modulators of melphalan produced 4.5- to 4.7-fold increases in tumor growth delay by the drug and were minocycline/sulindac, minocycline/mefenamic acid, and phenidone/sulindac. The most effective modulation of carmustine (BCNU) was obtained with minocycline/sulindac and minocycline/diflunisal leading to 2.8- to 3.1-fold increases in tumor growth delay by BCNU. Finally, the most effective modulation of radiation was obtained with minocycline/sulindac and phenidone/sulindac and resulted in 2.8- to 3.3-fold increases in tumor growth delay by radiation. The modulator combination that along with the cytotoxic therapies was most effective against metastatic disease was phenidone/mefenamic acid. There was no clear relationship between effective modulation of the cancer therapies and the degree of reduction in serum levels of prostaglandin E2 and leukotriene B4 by the agents in Lewis lung tumor bearing mice.

Animals↗

PubMed1994

Oxygenation of the rat 9L gliosarcoma and the rat 13672 mammary carcinoma with various doses of a hemoglobin solution.

Tumor oxygen tensions were measured using a computer controlled pO2 microelectrode in two preclinical solid tumor models, the rat 9L gliosarcoma and the rat 13672 mammary carcinoma. Tumor oxygenation profiles were determined under four conditions: 1) normal air breathing, 2) carbogen (95% O2/5% CO2) breathing, 3) after intravenous administration of a solution of ultrapurified polymerized bovine hemoglobin with normal air breathing and 4) after intravenous administration of a solution of ultrapurified polymerized bovine hemoglobin with carbogen breathing. Both tumors had severely hypoxic regions under normal air breathing conditions. Although carbogen breathing increased the oxygenation of the better oxygenated portions of the tumor, it did not impact on the severely hypoxic tumor regions. Administration of the hemoglobin solution was effective in increasing the oxygenation throughout both tumors under normal air breathing conditions. The addition of carbogen breathing to administration of the hemoglobin solution eliminated severe hypoxia in the 9L gliosarcoma and markedly reduced the severely hypoxic regions of the 13672 mammary carcinoma.

Animals↗