Biomedical subjects

B A Teicher

Publications and source records attributed to B A Teicher.

At least 37 records · Page 2Linked to original sources

PubMed1998

Sequence effect of irinotecan (CPT-11) and topoisomerase II inhibitors in vivo.

UNLABELLED: The DNA topoisomerases I and II are the target of several clinically important antineoplastic agents which produce DNA cleavage by stabilization of the covalent DNA-protein bond with resultant cell death after DNA synthesis is attempted. Depletion of the target topoisomerase and reciprocal changes in the other occur with drug treatment. PURPOSE AND METHODS: To develop empiric treatment regimens of combinations and sequences of agents directed against topoisomerase I (irinotecan/CPT-11) and II (etoposide and doxorubicin), in vivo studies were performed in mice bearing the EMT-6 mammary tumor to assess efficacy, host tolerance and the resultant biochemical changes in topoisomerase mRNA and protein. RESULTS: At 24 h after therapy, depletion of the target topoisomerase mRNA and protein with reciprocal increases in the alternate topoisomerase mRNA and, to a lesser extent, protein were noted. No therapeutic antagonism was found with any combination or sequence of agents, and therapeutic antagonism was noted with concurrent irinotecan/etoposide and sequential doxorubicin/irinotecan. Depletion of target topoisomerases by combined therapy beyond a threshold necessary for therapeutic efficacy produced no additional benefit. CONCLUSIONS: Antineoplastic therapy with combinations of topoisomerase I and II agents is feasible and may produce therapeutic synergy. The appropriate sequence may depend on the particular agents used. The rationale for such therapy, that topoisomerases I and II may have reciprocal and compensatory interactions, is supported by the biochemical data.

Animals↗

PubMed1998

Role of angiogenesis in the response to anticancer therapies.

Most solid tumors develop a vasculature (angiogenesis) as they increase in mass. Elucidation of the process by which blood vessels form in tumors has revealed the existence of both positive and negative regulators produced and secreted by many cell types. Angiogenesis has been identified as a critical process in mass expansion in most solid tumors, and numerous molecules have been described to be antiangiogenic agents. The question of whether antiangiogenic therapy is compatible with cytotoxic anticancer therapy has been addressed in the Lewis lung tumor with TNP-470 and minocycline along with radiation therapy and chemotherapy. Although the antiangiogenic therapy had no effect on the tumor size, administration of TNP-470/minocycline increased drug delivery to the tumor and tumor response to cytotoxic therapy increased implicating a potential role for these agents in the treatment of solid tumors.

Journal Article↗

PubMed1998

Acute in vivo resistance in high-dose therapy.

In the design of sequential high-dose chemotherapy regimens, the selection of antitumor alkylating agents to be included in each intensification and the interval between the intensifications are critical to the design of the therapy. The tumor cell survival assay and tumor growth delay assay using the murine EMT-6 mammary carcinoma were used as a solid tumor model in which to address these issues. Tumor-bearing mice were treated with high-dose melphalan or cyclophosphamide followed 7 or 12 days later by melphalan, cyclophosphamide, thiotepa, or carboplatin. After treatment with melphalan both 7 and 12 days later, the tumor was resistant to each of the four drugs studied. After treatment with cyclophosphamide both 7 and 12 days later, the tumor was resistant to melphalan and thiotepa but was not resistant to cyclophosphamide or carboplatin. To extend the interval between high-dose treatments to 14 and 21 days, after the first intensification the tumor was transferred to second hosts that were either drug-treated or not drug treated. When high-dose melphalan-treated tumors were treated with a second high dose of melphalan, the tumors were very resistant with the 14-day interval and less resistant with the 21-day interval. This small effect was evident in the bone marrow colony-forming unit, granulocyte-macrophage (CFU-GM), except in the hosts pretreated with melphalan. When high-dose cyclophosphamide-treated tumors were treated with a second high dose of cyclophosphamide, drug resistance was observed both with the 14-day and 21-day interval if the host was non-pretreated or was pretreated with melphalan, but not if the host was pretreated with cyclophosphamide. The same was true in the bone marrow CFU-GM. Tumor growth delay studies supported these findings in that treatment with high-dose cyclophosphamide, melphalan, thiotepa, and carboplatin resulted in less than additive tumor growth delay, whereas treatment with high-dose cyclophosphamide prior to treatment with high-dose melphalan, cyclophosphamide, thiotepa, or carboplatin resulted in additivity to greater-than-additive tumor growth delay. High-dose combination regimens required dose reduction of the drugs, which resulted in decreased tumor growth delays.

Animals↗

PubMed1998

Dose escalation of the hypoxic cell sensitizer etanidazole combined with ifosfamide, carboplatin, etoposide, and autologous hematopoietic stem cell support.

Multiple mechanisms of drug resistance contribute to treatment failure. Although high-dose therapy attempts to overwhelm these defenses pharmacologically, this approach is only successful in a fraction of treated patients. Many drug resistance mechanisms are shared between malignant and normal cells, but the expression of various drug resistance mechanisms associated with hypoxia is largely confined to tumor tissue. Thus, reversal of this mechanism is likely to provide a therapeutic advantage to the host. This study was designed to define the dose-limiting toxicities and maximum tolerated dose of etanidazole when it is given concurrently with high-dose ifosfamide, carboplatin, and etoposide (ICE), with hematopoietic stem cell support. The maximum tolerated doses of high-dose ICE were administered concurrently with dose escalations of etanidazole, a hypoxic cell sensitizer. All agents were given by 96-h continuous i.v. infusion beginning on day -7. Mesna uroprotection was provided. Autologous marrow and cytokine mobilized peripheral blood progenitor cells were reinfused on day 0. Granulocyte colony-stimulating factor was administered following reinfusion until the granulocytes recovered to > 1000/microliter. Fifty-five adults with advanced malignancies were enrolled in cohorts of five to nine patients. Four dose levels of etanidazole between 3 and 5.5 g/m2/day (12, 16, 20, and 22 g/m2 total doses) and two doses of carboplatin (1600 and 1800 mg/m2 total doses) were evaluated. Seven patients died of organ toxicity (13%); two each from veno-occlusive disease of liver and sepsis; and one each from sudden death, renal failure, and refractory thrombocytopenic hemorrhage. Five deaths occurred at the top dose level. One additional patient suffered a witnessed cardiorespiratory arrest from ventricular fibrillation and was resuscitated. Dose-dependent and largely reversible peripheral neuropathy was observed consisting of two syndromes: severe cramping myalgic/neuralgic pain, predominantly in stocking glove distribution, occurring between day -3 and day 0, and a sensory peripheral neuropathy with similar distribution peaking around day +60. The maximal achievable dose of etanidazole (16 g/m2 dose level) resulted in a mean serum level of 38 micrograms/ml (25-55 micrograms/ml). Etanidazole significantly enhanced host toxicity of high-dose ICE. Effective modulatory doses of etanidazole could not be given with acceptable toxicity using this schedule.

Adult↗

PubMed1998

Interaction of tomudex with radiation in vitro and in vivo.

The potential of the thymidylate synthase inhibitor, Tomudex to interact with ionizing radiation was assessed in vitro and in vivo in comparison with 5-fluorouracil. A concentration of 1 microM Tomudex decreased the shoulder of the radiation survival curves for normally oxygenated and hypoxic human HT-29 colon carcinoma cells and human SCC-25 head and neck squamous carcinoma cells, resulting in enhancement ratios of 10 and 2.8 for normally oxygenated and hypoxic HT-29 cells at 5 Gray, respectively, and enhancement ratios of 19.5 and 2.7 for normally oxygenated and hypoxic SCC-25 cell at 5 Gray, respectively. Two schedules of Tomudex administered to animals bearing the Lewis lung carcinoma resulted in additive tumor growth delay with the fractionated radiation therapy. In nude mice bearing the HT-29 colon carcinoma grown as a xenograft, administration of Tomudex daily for 5 days on a 1 or 2-week schedule resulted in increased tumor growth delay along with fractionated radiation therapy on the same schedules. However, administration of Tomudex intermittently on a 2-week schedule appeared to be more interactive with daily fractionated radiation therapy on the 2-week schedule. In each assay, the results obtained with Tomudex were equal to or exceeded those obtained with 5-fluorouracil. These findings indicate that clinical trial of Tomudex along with fractionated radiation therapy is warranted.

Animals↗

PubMed1998

Biochemical characterization of in vivo alkylating agent resistance of a murine EMT-6 mammary carcinoma. Implication for systemic involvement in the resistance phenotype.

While cancer drug resistance has been extensively studied in cell culture, little is known about more clinically relevant in vivo resistance. The in vivo resistance of a murine mammary carcinoma EMT-6 to alkylating agents was demonstrated in the present study to be associated with multiple biochemical changes. These included an up to 1.5-fold increase in activity of phase II drug metabolizing enzymes (DMEs), such as glutathione (GSH), glutathione reductase (GR), glutathione S-transferase (GST), glutathione peroxidase (GPX) and aldehyde dehydrogenase (ALDH), and an up to 88% decrease of phase I DME activity [7-ethoxycumarin O-deethylase (ECOD), P450 reductase (PR)] in the resistant tumors compared with the parental tumor. Transplant of either parental or resistant tumors to mice was accompanied by a decrease of both phase I and phase II DME activity in the livers of female Balb/C mice compared with the non-tumor mice. Moreover, at the protein level, while cytochrome P450 (CYP) IIB1/2 in the liver of mouse bearing both the sensitive and the resistant tumor was significantly diminished compared to that in the liver of non-tumor control mouse in Western analysis, there was actually an increase of this protein in the liver of the host bearing either of the two resistant tumors compared to that of the sensitive tumor-bearing animal. Although this in vivo resistance phenotype is not expressed in cell culture, the profile of most of the enzyme changes in the resistant tumors remained similar in in vitro culture of the isolated tumor cells. Collectively, these results demonstrate that this in vivo alkylating agent resistance is associated with multiple changes of both phase I and phase II DMEs in the resistant tumors, and some of these, such as CYP IIB1/2 protein are further altered in the resistant tumor-bearing mouse liver, suggesting a potential role of systemic factors in this resistance phenotype.

7-Alkoxycoumarin O-Dealkylase↗

PubMed1997

Reversal of in vivo drug resistance by the transforming growth factor-beta inhibitor decorin.

Transforming growth factor-beta (TGF-beta) has been implicated in the in vivo resistance of the EMT-6/CTX and EMT-6/ CDDP murine mammary tumors. Both of these tumors have a higher number of intratumoral vessels than the EMT-6/ parent tumor. Animals bearing the resistant tumors have higher plasma levels of TGF-beta than animals bearing the parent tumors; however, upon treatment with cytotoxic therapies there is a greater rise in plasma TGF-beta levels in animals bearing the parent tumor than in animals bearing the resistant tumors. In situ hybridization for TGF-beta mRNA and immunohistochemical staining for TGF-beta protein showed that the resistant tumor levels of this growth factor are higher than those of the parent tumor prior to treatment; however, after cytotoxic therapy the increase in TGF-beta is greater in the parent tumor than in the resistant tumors. Treatment of tumor-bearing animals with the naturally occurring TGF-beta inhibitor decorin did not alter the sensitivity of the parent tumor to cyclophosphamide or to CDDP as determined by tumor cell survival assay. However, administration of decorin increased the sensitivity of the EMT-6/CTX tumor to cyclophosphamide and of the EMT-6/CDDP tumor to CDDP so that the drug resistance of these tumors was nearly ablated. A similar pattern was observed in the drug response of the bone marrow granulocyte-macrophage colony-stimulating factor of animals bearing each of the 3 tumors.

Animals↗

PubMed1997

Dynamics of tumor oxygenation, CD31 staining and transforming growth factor-beta levels after treatment with radiation or cyclophosphamide in the rat 13762 mammary carcinoma.

PURPOSE: Tumors are dynamic tissues that undergo marked molecular, biochemical, and physiologic changes in response to cytotoxic anticancer therapies. Understanding the changes in tumor oxygenation and transforming growth factor-beta expression may allow improved treatment regimens to be developed. METHODS AND MATERIALS: The effects of a single dose of radiation therapy (20 Gy) or a single dose of chemotherapy (cyclophosphamide, 250 mg/kg) on several molecular and physiologic parameters of the rat 13762 mammary carcinoma growing subcutaneously in female Fischer 344 rats were explored. RESULTS: Treatment of the tumor-bearing animals with 20 Gy of radiation killed about two logs (99%) of the 13762 tumor cells, and treatment with cyclophosphamide (250 mg/kg) killed about 1.5 logs (95%) of the 13762 tumor cells. Hypoxia, as determined by a pO2 electrode, initially decreased in the tumors of treated animals until 6 h. posttreatment and then increased, so that 24 h. after administration of the radiation therapy or the chemotherapy the number of intratumoral vessels as determined by CD31 staining increased until about 24 h after cytotoxic therapy. Transforming growth factor-beta1, measured by radioimmunoassay, peaked in the serum between 6 h and 18 h and again between 72 h and 96 h after radiation therapy and peaked in the tumor at 24 h and again at 72 h after radiation therapy. The first serum peak after cyclophosphamide was 3 h after drug injection, with second peaks at 36 h and 48 h after drug administration. In the tumor, transforming growth factor-beta1 peaked between 6 h and 8 h after drug administration and again 36 h and 72 h after drug. Apoptosis was maximal 6 h after 20 Gy and 24 h after cyclophosphamide. Vascular endothelial growth factor was also increased in tumors after cytotoxic therapy. CONCLUSIONS: These changes in the tumor physiologic status are sufficient to protect the tumor from a second cytotoxic insult administered days afterwards and to result in a restructuring of the tissue.

Animals↗

PubMed1997

Analogues of N alpha-(4-amino-4-deoxypteroyl)-N delta-hemiphthaloyl-L-ornithine (PT523) modified in the side chain: synthesis and biological evaluation.

Four heretofore undescribed side chain analogues of N alpha-(4-amino-4-deoxypteroyl)-N delta-hemiphthaloyl-L-ornithine (PT523, 4) were synthesized via straightforward methods of antifolate chemistry, and their properties were compared with those of PT523 and two related compounds with the aim of defining the contribution of the hemiphthaloyl-L-ornithine moiety to the exceptional in vitro antitumor activity of this novel non-polyglutamatable aminopterin analogue. The IC50 values of N alpha-(4-amino-4-deoxypteroyl)-N beta-hemiphthaloyl-L-2,3-diaminopropanoic acid (10) and N alpha-(4-amino-4-deoxypteroyl)-N gamma-hemiphthaloyl-L-2,4- diaminobutanoic acid (9) against A549 human non-small-cell lung carcinoma cells in culture were 23 and 22 nM, whereas those of PT523 and N alpha-(4-amino-4-deoxypteroyl)-N epsilon-hemiphthaloyl-L-lysine (8) were 1.3 and 5.2 nM. A decrease in the in vitro activities of 8 and 9 relative to PT523 was also observed against the panel of cell lines used by the National Cancer Institute to screen new drugs. However the potency of 8 and 9 remained several times greater than that of the historical control methotrexate against many of the cell lines in the screening panel. In an in vivo tumor model, SCC-VII murine squamous cell carcinoma, 9 and methotrexate were well tolerated as 5-day continuous infusions at doses of 0.52 and 0.75 mg/kg/day, whereas the highest tolerated dose of PT523 on this schedule was 0.19 mg/kg/day, in agreement with its lower IC50 in culture. To assess the importance of the hemiphthaloyl group in PT523, N alpha-(4-amino-4-deoxypteroyl)-N delta-isophthaloyl-L-ornithine (11), N alpha-(4-amino-4-deoxypteroyl)-N delta-terephthaloyl-L-ornithine (12), and N alpha-(4-amino-4-deoxypteroyl)-N delta-(4,5-dichlorohemiphthaloyl)-L-ornithine (13) were also synthesized. The IC50 values of 11 and 12 against A549 cells were 45 and 3300 nM, as compared with 1.3 nM for PT523 and 23 nM for methotrexate. In a clonogenic assay against SCC25 human squamous cell carcinoma cells, the IC50 values of 11 and 12 were 2.9 and 72 nM, as compared with 0.3 nM for PT523 and 27 nM for methotrexate. Thus, activity was decreased by moving the aromatic carboxyl group in PT523 to the meta position and was further diminished by moving it to the para position. The IC50 of the halogenated analogue 13 against SCC25 human head and neck squamous carcinoma cells was 18 nM, suggesting lack of tolerance for this 4,5-disubstitution in the phthaloyl moiety. Our results suggest that the combination of a hemiphthaloyl group and three CH2 groups in the side chain are critical determinants of the potent in vitro activity of PT523.

Animals↗

PubMed1997

Interlaboratory variation in oxygen tension measurement by Eppendorf "Histograph" and comparison with hypoxic marker.

BACKGROUND AND OBJECTIVES: The median of pO2 values in tumor measured by Eppendorf "Histograph" with a needle-type electrode has been used as a prognostic indicator in cancer patients. However, it is not established that a pretreatment measured pO2 value can be used as a universal predictor of local control probability, because the variation in pO2 values, especially in hypoxic tissue, among institutes may not allow comparison of measured "absolute pO2 values." The purpose of this study was to examine the variation in oxygen tension measurement by Eppendorf "Histograph" among six laboratories using a single batch of mice and tumors and the same detailed protocol. These results were also compared to the immunohistochemical staining of 2-nitromidazole adducts. METHODS: C3H mice bearing FSaII murine fibrosarcoma subcutaneously were shipped to all laboratories, and the oxygen status in tumors and in normal subcutis was examined using Eppendorf "Histograph" and immunohistochemical hypoxic marker. RESULTS: All laboratories showed that the FSaII tumor was hypoxic with at least 77% of measured points under 10 mmHg in pO2 and with a median pO2 value less than that of normal subcutis. These results were further confirmed immunohistochemically. These findings are interpreted as evidence that the pO2 values measured by Eppendorf "Histograph" can be useful. However, the median values of tumor pO2 varied from 1.5 mmHg to 5.6 mmHg among the laboratories, and pO2 of normal subcutis also varied from 28 mmHg to 38 mmHg. There were also significant differences in hypoxic fraction, defined as the fraction under a given oxygen partial pressure (i.e., under 2.5, 5, or 10 mmHg), among institutes. CONCLUSIONS: Caution needs to be exercised in using the absolute, median, or distribution of pO2 values measured by the Eppendorf "Histograph" to compare the data between laboratories or to predict the radiation response in an individual subject.

Animals↗

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↗

PubMed1997

Preclinical studies of the combination of angiogenic inhibitors with cytotoxic agents.

TNP-740, minocycline, suramin and genistein have demonstrated antiangiogenic activity in various experimental systems. The effect of these agents alone and in two agent combinations on the number of intratumoral vessels and response to cytotoxic anticancer therapies was assessed in animals bearing the Lewis lung carcinoma. Treatment with each of the antiangiogenic agents alone and in two agent combinations decreased the number of intratumoral vessels visualized by CD31 or Factor VIII staining to 30% to 50% of the number in the untreated control tumors. In general, the antiangiogenic agents are more effective adjuvants to cytotoxic therapies when used as two agent combinations than as single agents. The most effective antiangiogenic combinations were: TNP-470/minocycline > TNP-470/genistein > TNP-470/suramin. The increases in the response of the primary tumor to cyclophosphamide, adriamycin, CDDP, BCNU, x-rays or 5-fluorouracil and the lung metastases occur to about the same level with the addition of antiangiogenic agents to the therapies. With the treatment combination TNP-470/minocycline/cyclophosphamide 40% of the animals were cured. The results of these studies indicate that antiangiogenic agents can be very useful additions to treatment regimens for solid tumors.

Animals↗

PubMed1997

Apoptosis and clonogenic cell death in PC3 human prostate cancer cells after treatment with gamma radiation and suramin.

Suramin is a novel cytostatic/cytotoxic agent that is currently undergoing clinical trials in the treatment of hormone- and chemo-refractory tumors. Its unusual mechanism of action and its activity against prostate cancer raise the possibility that it could be particularly suitable for combined-modality treatment of prostate cancer. PC3 human prostate cancer cells were used as an in vitro model to test the possible interaction between suramin and ionizing radiation. Treatment with gamma radiation resulted in detachment of PC3 cells from the monolayer, and the detached cells exhibited internucleosomal DNA fragmentation characteristic of apoptosis. Low concentration of suramin (50-100 micrograms/ml, 35-70 microM) increased spontaneous as well as radiation-enhanced apoptosis. However, suramin inhibited spontaneous and radiation-enhanced apoptosis at 300 micrograms/ml (210 microM), a concentration that is more commonly used in the clinic. At this concentration suramin inhibited DNA fragmentation induced by chemotherapeutic drugs as well. The effect of suramin on inhibition of DNA fragmentation was reversible if the suramin was removed 24 h after irradiation. Despite inhibition of radiation-induced apoptosis by 300 micrograms/ml suramin (from 5% to 2.9% at 48 h), clonogenic cell death was enhanced by the combination of suramin and radiation. The effects of radiation and suramin on clonogenic cell survival appeared to be additive by isobologram analysis at clinically relevant radiation doses. Continuous exposure to a lower concentration of suramin (100 micrograms/ml) during the clonogenic assay period was as effective in decreasing clonogenic survival as 48 h exposure to 300 micrograms/ml suramin in decreasing clonogenic survival. Our data indicate that, when used in combination with radiation, suramin may be effective at concentrations that are lower than those required for efficacy as a single agent.

Antineoplastic Agents↗

PubMed1997

Optimal scheduling of interleukin 12 and chemotherapy in the murine MB-49 bladder carcinoma and B16 melanoma.

The antitumor activity of interleukin (IL)-12, a naturally occurring cytokine, has been demonstrated in several murine solid tumors. Animals bearing established B16 melanoma or MB-49 bladder carcinoma were used to study the most effective scheduling of recombinant murine IL-12 (rmIL-12), along with systemic chemotherapy. rmIL-12 (0. 45, 4.5, or 45 microgram/kg) was more effective as a single agent when administered to mice bearing the MB-49 bladder carcinoma at the highest dose for 11 doses rather than for 5 doses. In combination with chemotherapy (Adriamycin, cyclophosphamide, or 5-fluorouracil), rmIL-12 administration did not increase the toxicity of the chemotherapy, and there was increased antitumor activity with each rmIL-12-drug combination. Administering rmIL-12 (45 microgram/kg) on days 4-14, along with Adriamycin, cyclophosphamide, or 5-fluorouracil on days 7-11, resulted in 2.2-2.7-fold increases in tumor growth delay, compared with the chemotherapy alone against the primary tumor, and a marked decrease in the number of lung metastases on day 20. Because the B16 melanoma grows more slowly than the MB-49 bladder carcinoma, allowing multiple courses of chemotherapy, cyclophosphamide could be administered. The rmIL-12 (45 microgram/kg)-cyclophosphamide combination regimen that was most effective overlapped 2 days with the terminal portion of the chemotherapy treatment. There was a parallel increase in the response of the primary tumor and metastatic disease to the lungs. Administration of rmIL-12 to animals bearing the MB-49 bladder carcinoma or the B16 melanoma was compatible with coadministration of chemotherapy at full dose without additional toxicity.

Animals↗

PubMed1996

Interaction of interleukin-11 with cytotoxic therapies in vitro against CEM cells and in vivo against EMT-6 murine mammary carcinoma.

Interleukin-11(rhIL-11) is a cytokine that has been shown to enhance the recovery of bone marrow and intestinal crypt cells after cytotoxic insult with radiation or anticancer drugs. The current study examined the effects of rhIL-11 on the response of CEM human lymphoblastic leukemia cells and on the EMT-6 murine mammary carcinoma in vivo to cytotoxic anticancer therapies. Exposure of CEM cells to rhIL-11 for 24 hr did not alter the cytotoxicity of melphalan or radiation, increased the cytotoxicity of CDDP (100 muM) and 4-hydroperoxycyclophosphamide (50 betaM) and decreased the cytotoxicity of 5-fluorouracil and ara-C toward the cells. Treatment of mice bearing the EMT-6 tumor with rhIL-11 twice daily for 4 days prior to and the day of cytotoxic therapy resulted in no significant change in the tumor cell killing or bone marrow CFU-GM killing by melphalan, cyclophosphamide, thiotepa, CDDP, radiation, 5-fluorouracil or ara-C. Administration of rhIL-11 twice per day on days 7-18 to EMT-6 tumor bearing animals receiving high dose chemotherapy (melphalan, thiotepa or cyclophosphamide) as a single dose on day 7 followed by mobilized peripheral blood cells on day 8 and rhG-CSF on days 8-20, tended to prolong the tumor growth delay produced by the drugs. This rhIL-11 treatment also resulted in a more rapid recovery of white blood cells and granulocytes in the animals. Furthermore, animals treated with rhIL-11 had improved survival rates compared with animals receiving all other normal tissue support without rhIL-11.

Animals↗

PubMed1996

Cure of multidrug-resistant human B-cell lymphoma xenografts by combinations of anti-B4-blocked ricin and chemotherapeutic drugs.

The CD-19-directed immunotoxin anti-B4-blocked ricin (anti-B4-bR) is currently in clinical trials for the treatment of B-cell malignancies. To explore the potential of using anti-B4-bR with chemotherapy protocols we tested the in vivo efficacy of the immunotoxin in combination with two multi-drug chemotherapeutic regimens in severe combined immunodeficient (SCID) mice bearing disseminated tumors of the multidrug-resistant human B-cell lymphoma Namalwa/mdr-1. In cytotoxicity studies in vitro, combinations of the immunotoxin with cisplatin produced supra-additive killing effects on both Namalwa and Namalwa/mdr-1 cells, whereas anti-B4-bR combined with 4-hydroperoxy-cyclophosphamide caused additive killing of both cell lines. In vivo cyclophosphamide, cisplatin, vincristine, doxorubicin, and etoposide as single agents, were effective in prolonging the survival of SCID mice burdened with the Namalwa tumor, whereas only cyclophosphamide and cisplatin were effective on Namalwa/mdr-1 tumors. Treatment of Namalwa/mdr-1-bearing mice with anti-B4-bR alone or with the drug combination CHOE (consisting of cyclophosphamide, vincristine, doxorubicin, and etoposide) alone increased the lifespan of the tumor-burdened mice by 58% and 73%, respectively. However, treatment with five daily bolus intravenous injections of anti-B4-bR followed by CHOE increased the lifespan by 173%, and 20% of the mice were cured. The drug combination CCE (cyclophosphamide, cisplatin, and etoposide) alone could increase the lifespan of the Namalwa/mdr-1 tumor-burdened mice by 129% compared with untreated controls. Combination therapy with anti-B4-bR and CCE produced long-term cures in 50% of the tumor-burdened mice. These results suggest that anti-B4-bR in combination with current multidrug regimens may constitute a highly efficacious modality for the treatment of drug-resistant B-cell malignancies.

Animals↗

PubMed1996

Effect of DNA conformation on cisplatin adduct formation.

The anticancer drug cis-diamminedichloroplatinum(II) (cisplatin) has been shown previously to form adducts preferentially within internucleosomal or linker DNA rather than to DNA within the nucleosome. To determine whether other "open" regions of chromatin have an increased affinity for cisplatin, adduct formation within specific chromatin domains was analyzed. There was a significant increase in cisplatin-DNA adduct formation for DNA associated with the nuclear matrix (NM) compared with other chromatin domains and total unfractionated DNA. In contrast, treatment of the same cells with trans-diamminedichloroplatinum(II) (transplatin) did not result in preferential adduct formation. These findings led to the hypothesis that it might be possible to alter DNA to make it a more favorable target for cisplatin. The effect of arginine butyrate on cisplatin-DNA adduct formation was analyzed in human cancer cells. The combination of arginine butyrate and cisplatin resulted in a concentration-responsive increase in cisplatin-DNA adduct formation in PC-3 cells and an overall increase in cisplatin-DNA adduct formation in three other human cancer cell lines. The same combination also resulted in a significant increase in drug-induced cytotoxicity at a low concentration of cisplatin. These results suggest that chromatin configuration can affect cisplatin adduct formation.

Antineoplastic Agents↗

PubMed1996

High-dose therapy/stem cell support: comparison of mice and humans.

A murine high-dose therapy/stem cell support model is described using female BALB/c mice bearing the EMT-6 mammary carcinoma. Peripheral blood cells were prepared in syngeneic donor animals mobilized by treatment with cyclophosphamide and rhG-CSF. The most effective support regimen includes administration of fluid by gavage, rhG-CSF twice per day for 12 days and peripheral blood cells administered i.v. on the day after cytotoxic therapy. Dose escalations of 2.2- to 13-fold over the usual conventional dose were possible in mice treated with single doses of cyclophosphamide, carmustine, melphalan, thiotepa, carboplatin or total body radiation, which compare favorably with dose escalations achievable in humans. Depletion and recovery rates of white blood cells and granulocytes in the mice were similar to those seen in humans. Rapid weight loss is a major factor in limiting further dose escalation. Single high-dose therapy with cyclophosphamide, melphalan, thiotepa and carboplatin, but not 5-fluorouracil, produced longer tumor growth delays than standard regimens of the same drugs. For melphalan and thiotepa, there was a direct correlation between drug dose, tumor growth delay and tumor surviving fraction. With cyclophosphamide, the tumor growth delay with high-dose therapy was greater than expected from the dose increase and the tumor surviving fraction data.

Animals↗