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R T Dorr

Publications and source records attributed to R T Dorr.

At least 91 records · Page 5Linked to original sources
PubMed1991

Additional nucleotide derivatives of mitosenes. Synthesis and activity against parental and multidrug resistant L1210 leukemia.

Cytidine 5'-monophosphate and 5'-ara-CMP conjugates of 2,7-diaminomitosene, with the phosphate groups linked to C-1, were prepared by treating mitomycin C with the appropriate nucleotides. 5'-UMP conjugates were prepared from mitomycin A, 7 (M-83), and 8 (BMY-25282) by similar procedures. A conjugate could not be prepared from mitomycin C and 6-MPRP, but a sulfur-linked derivative was made with 6-MP ribonucleoside. The corresponding 1-hydroxy-2-aminomitosenes were prepared from the parent mitomycin analogues for structure-activity comparisons. All compounds were tested against L1210 murine leukemia in the MTT tetrazolium dye assay. In general, the conjugates were less potent than the parent mitomycins; however 5'-ara-CMP conjugate 14 derived from mitomycin C was more potent than the parent compound or any mitomycin tested except mitomycin A. It also was more potent than ara-C. This result establishes the value of this approach to prodrugs, at least in cell culture. Against a multi-drug-resistant L1210 cell line, all of the conjugates derived from mitomycin C were more potent than the parent compound. 6-Mercaptopurine ribonucleoside conjugate 15 was more active against the resistant cells than it was against the parental cell line.

Animals↗
PubMed1991

Structure-activity relationships for mitomycin C and mitomycin A analogues.

A set of 30 mitomycin C and mitomycin A analogues, including five new compounds, was screened against three different solid human tumor cell lines using the MTT tetrazolium dye assay. A statistically significant correlation among antitumor activity, quinone reduction potential (E1/2), and the logarithm of the partition coefficient (log P) was obtained, with the most easily reduced and the most lipophilic compounds being the most potent. When these analogues were separated into mitomycin C and mitomycin A subsets, the former gave a correlation only with E1/2, whereas the latter (which differ little in their E1/2 values) gave a correlation only with log P. These correlations are in contrast to those made in the P388 leukemia assay in mice wherein the most active mitomycin C and mitomycin A analogues were the most hydrophilic ones. When the same compounds were tested against P388 leukemia cells in the MTT assay, the results were the same as those of the solid tumor assays. Thus, the substantial differences in relative potencies of mitomycins are related not to the kind of tumor cell, but to the type of assay performed, cell culture versus whole animal. No correlation was found between antitumor potency in the cell culture systems and calculated relative DNA binding strengths, probably because the limiting factors in antitumor potency of mitomycins appear to be tumor cell uptake (log P) and/or bioreductive activation (E1/2).

Animals↗
PubMed1991

Structure-activity studies of antitumor agents based on pyrrolo[1,2-a]benzimidazoles: new reductive alkylating DNA cleaving agents.

Described herein are structure-activity studies of new antitumor agents based on the pyrrolo[1,2-a]benzimidazole (PBI) ring system. These compounds were designed as new DNA cross-linkers mimicking the mitomycin antitumor agents. Actually, the PBI derivatives were found to have anthracycline-like features: (i) shared cross resistance with doxorubicin in a human myeloma line, (ii) cardiotoxicity, and (iii) excellent DNA strand cleaving capability. The DNA strand cleavage is thought to result from reductive alkylation of DNA followed by the generation of reactive oxygen radicals. The best antitumor agent studied is 6-N-aziridinyl-3-hydroxy-7-methyl-2,3-dihydro-1H-pyrrolo- [1,2-a]benzimidazole-5,8-dione 3-acetate (PBI-A), which possesses nanomolar IC50 values against various human ovarian and colon cancer cell lines.

Alkylation↗
PubMed1991

Comparison of cytotoxicity in heart cells and tumor cells exposed to DNA intercalating agents in vitro.

A new approach to antitumor analog selection was evaluated using in vitro cytotoxicity assays in tumor cells and heart cells. Eight anthracycline antibiotics and five non-anthracycline DNA intercalating agents were separately exposed to human 8226 myeloma cells and neonatal rat heart myocytes in vitro. Survival was measured after six days of culture by the MTT dye method for tumor cells and by ATP content for heart cells. Inhibitory drug concentrations in 50% of cells (IC50) were determined from log-linear dose-response curves for each agent. The IC50 values in the tumor cells ranged from 0.002 micrograms/ml for idarubicin to 3.5 micrograms/ml for the primary metabolite of doxorubicin, doxorubicinol. In contrast, IC50 values for anthracyclines in rat heart cells averaged approximately 357-fold higher than in the tumor cells. The heart cell/tumor IC50 ratio was 114.4 for the parent anthracycline doxorubicin. Compounds with poor cytotoxic selectivity for tumor cells included doxorubicinol, amonafide, amsacrine and bisantrene. Compounds with reduced cardiotoxicity included the anthracyclines daunorubicin (IC50 ratio of 550), esorubicin (IC50 ratio of 1500) and the anthracene derivative mitoxantrone (IC50 ratio of 500). These results show that simultaneous comparisons of cytotoxicity in heart cells and tumor cells can identify agents such as daunorubicin and mitoxantrone which are known to produce less cardiac toxicity in vivo. With further testing, this methodology may be applicable to preclinical screening programs to select active DNA intercalating agents with low cardiotoxic potential.

Adenosine Triphosphate↗
PubMed1991

In vitro cytotoxicity against fresh human tumors and P388 leukemia predicts the differential in vivo activity of a series of anthracene anticancer drugs.

To date, random anticancer drug screening has proven to be relatively inefficient and non-specific with respect to selecting active compounds for most tumor types (except for leukemia/lymphoma). Although large numbers of compounds from diverse sources were evaluated for many years in the P388 mouse leukemia model, only a few clinically useful drugs have been identified by this in vivo screening method. Thus, there is intense interest in the development of more effective in vitro screening models for new anticancer drugs. In the present paper we have compared the discriminating power for fresh human tumors from patients, human tumor cell lines developed from 11 patients and murine P388 leukemia in tumor colony forming assays as indicators of cytotoxicity for a series of anthracene antitumor agents. Two of a series of 21 novel bisantrene analogs, R6 (N,N1-bis[2-(dimethylamino)ethyl]-9,10-anthracene-bis(methylamine)) and R26 (N,N1-bis(1-ethyl-3-piperidinyl)-9,10-anthracene-bis(methylamine] produced significant cytotoxicity against the 11 human tumor cell lines and were therefore selected for additional in vitro and in vivo studies. R26 was specifically selected for further testing since it had similar in vitro potency as mitoxantrone, but showed no cross-resistance against mitoxantrone-resistant WiDr colon or doxorubicin-resistant 8226 myeloma cell lines. In contrast to the cell line data, only of the 22 fresh human tumors showed significant in vitro sensitivity (i.e. less than 50% survival of tumor colony forming units) to either R6 or R26 tested at high concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Cutaneous ulceration due to contrast extravasation. Experimental assessment of injury and potential antidotes.

Severe cutaneous ulceration may occur as a result of contrast media extravasation. We established a definitive animal model for assessing the cutaneous toxicity of commonly employed agents and used this model to evaluate possible antidotes to the effects of contrast media extravasation. The contrast agents studied were: meglumine/sodium diatrizoate 76%, meglumine iothalamate 60% and 43%, meglumine/sodium ioxaglate 60%, iohexol 350, and iopamidol 370, in varying volumes and osmolalities. Hypertonic saline (950 and 1900 mOsm/kg) also was injected. Agents were injected intradermally into BALB/c mice. The higher osmolality agents produced dose-dependent skin ulcerations. The lower osmolality agents failed to produce any skin lesions after the same volume doses. Hypertonic saline produced skin toxicity in a dose-dependent fashion similar to hyperosmolar contrast agents. Three antidotes were tested: hyaluronidase, topical heat, and topical cold. Hyaluronidase significantly reduced skin toxicity when injected immediately following contrast injection. Cold also significantly reduced skin toxicity, while heat caused no improvement.

Animals↗
PubMed1991

Chemoprotectants for cancer chemotherapy.

Maximal dosing of cytotoxic chemotherapy drugs is often limited by the development of severe nonmyelosuppressive toxicities. Numerous studies have demonstrated that sulfur-containing nucleophiles can antagonize the dose-limiting effects of alkylating agents on the genitourinary tract. Examples include the use of sodium thiosulfate to prevent cisplatin-induced renal tubular necrosis and the use of sulfhydryl-containing compounds like N-acetylcysteine and 2-mercaptoethanesulfonate (mesna) to block oxazophosphorine-induced bladder toxicity. Mesna does not block the antitumor action of oxazophosphorines due to its rapid formation of the inactive dimer dimesna in the bloodstream. The active monomer is selectively reduced from dimesna in renal tubule cells, thereby limiting the inactivation of toxins like acrolein to the genitourinary tract. Recent clinical trials suggest that oral mesna has adequate bioavailability (roughly 50% by urinary thiol measurements) to prevent urotoxicity in high-dose ifosfamide regimens. In addition, mesna is stable in aqueous oral formulations. This may facilitate more convenient oral mesna dosing in protocols using high-dose cyclophosphamide or ifosfamide. Whereas agents like mesna and sodium thiosulfate complex directly with activated (electrophilic) alkylator species, chemoprotectants for the anthracyclines appear to complex with metal cofactors like iron, which are required for the production of cardiotoxicity. Several ethylenediaminetetraacetic-like agents have been evaluated, and a water-soluble piperazinyl derivative, ICRF-187, is currently undergoing clinical evaluation in patients receiving large cumulative doxorubicin doses. An initial clinical trial suggests that ICRF-187 can prevent doxorubicin-induced cardiomyopathy. As with mesna, ICRF-187 does not block the myelosuppressive or the antitumor effects of doxorubicin. Overall, these studies show that site-selective chemoprotection is now feasible for at least two major classes of anticancer agents.

Antibiotics, Antineoplastic↗
PubMed1990

Antidotes to vesicant chemotherapy extravasations.

The foregoing sections have reviewed the experimental studies and clinical anecdotes describing potential pharmacologic antidotes to extravasations of vesicant anticancer agents. Numerous prior reviews have also suggested specific antidotes or very conservative, non-pharmacologic approaches. Many antidotal approaches to extravasation have not been experimentally validated and thus, few 'antidotes' share a rationale which is founded on positive experimental and clinical studies. However, using this criteria, a few active antidotes can be distilled from the literature. These are outlined in Table 6. These antidotes include isotonic (1/6 M) sodium thiosulfate for mechlorethamine (and optionally for cisplatin), hyaluronidase for the vinca alkaloids (and optionally for epipodophyllotoxins such as etoposide), and cooling with very topical DMSO and low dose hydrocortisone for the anthracyclines. For the alkylating agent mitomycin C, topical DMSO has been effective experimentally but has not yet received clinical validation, at least in published studies. Nonetheless, the severity of mitomycin C ulcerations and the documented safety of topical DMSO in the small series of doxorubicin extravasation patients argues for its use when mitomycin extravasates in the clinic. Furthermore, except for DMSO, all of these extravasation antidotes are listed in the official FDA-approved package inserts for each vesicant agent. Thus, the inserts for vincristine and vinblastine specify hyaluronidase, for doxorubicin, glucocorticosteroids, and for mechlorethamine, sodium thiosulfate. New studies are clearly needed to clarify the role of topical DMSO with anthracyclines and mitomycin C. In addition, efforts should be made to begin clinical development of radical dimers such as DHM3 which can directly inactivate quinone-containing vesicants like doxorubicin and mitomycin C. Although the incidence of chemotherapy extravasation may be lessened with vascular access devices, it nonetheless, continues to comprise a serious and highly litigious area of oncology practice. This commands continued extravasation intervention studies and diligent prevention when ever possible.

Animals↗
PubMed1990

Alkylation of DNA by C-10 of 2,7-diaminomitosene.

Mitomycin C and certain analogues alkylate DNA with their C-1 position and cross-link it by a second alkylation involving C-10. We now show that monoalkylation by C-10 (carbamate group) can occur for mitosene analogues that have no reactive C-1 functionality. Sodium dithionite reduction of 2,7-diaminomitosene or 2,7-diamino-1-hydroxymitosene in the presence of calf thymus DNA resulted in alkylation of the DNA to the extent of one molecule per 14 and 11 bases, respectively, although no covalent binding was observed on catalytic reduction. Reduction of each of these mitosenes by sodium dithionite in the presence of 2'-deoxyguanosine gave monoalkylation on the 2-amino group of this nucleotide. The 2,7-diaminomitosenes inhibited L-1210 leukemia cell colony formation in vitro at concentrations 3-4-fold greater (less potent) than mitomycin C. DNA single-strand breaks were also produced by each mitosene, but these lesions did not correlate with cytotoxicity and were less prominent than breaks produced by another monofunctional alkylating agent, methyl methanesulfonate. Mitosene-induced DNA strand breaks are probably due to excission-repair endonuclease activity and not from oxygen free radicals produced by redox cycling of the quinone moiety. There was no evidence of DNA-DNA cross-links by either 2,7-diaminomitosene.

Alkylation↗
PubMed1990

Mitomycin, ifosfamide, and mesna in the treatment of lung cancer.

Observations have been made of the multiple-drug resistance phenomenon in mitomycin-exposed cells in vitro. Collateral resistance to anthracyclines and Vinca alkaloids was demonstrated in mitomycin carbon-treated 1-1210 cells in vitro. However, because it has also been found that this resistance can be reversed with agents such as verapamil and progestogens, it may be possible to effect a similar reversal in vivo. A study is currently being performed in patients with colorectal cancer, in which the potential for reversal is being tested. The pharmacokinetics of ifosfamide result in high cytotoxic specificity which, along with its therapeutic range, makes it a particularly active agent in the treatment of non-small cell lung cancer. Its urotoxicity is effectively controlled by the coadministration of mesna, a uroprotective agent.

Animals↗
PubMed1989

High levels of doxorubicin in the tissues of a patient experiencing extravasation during a 4-day infusion.

A 56-year-old patient with multiple myeloma experienced an extravasation of doxorubicin (DOX) and vincristine administered as a 96-hour infusion. An unknown quantity of solution (2.1 mg/ml of DOX and 0.1 mg/ml of vincristine) extravasated into the medial aspect of the right upper arm. This was caused by the axillary blockage of a 14-inch, 18-gauge catheter that had been inserted through the antecubital fossa. The only physical complaint mentioned by the patient was a dull muscle ache. No local swelling or redness was apparent until 2 weeks after the extravasation occurred, at which time surgical debridement yielded a 9.2 x 4 x 2-cm section of fascia and thrombosed vein with a normal-appearing margin. A high performance liquid chromatography analysis of different tissue areas in the surgical specimen yielded DOX levels of 1.25 to 7.94 micrograms/g of wet tissue weight. These levels are approximately tenfold higher than those of any previous extravasation reports. Slightly lower levels of the DOX aglycone (but no doxorubicinol) were recovered from these tissues. An important finding was the DOX level of 2.7 micrograms/g in the margin of the specimen, predicting a need for further surgery. Indeed, a second debridement was performed 1 week later, followed by a split thickness skin graft. Although the myeloma remains in clinical remission, use of the effected right arm is limited primarily by skin contracture at the graft site. This case demonstrates that high DOX levels can be deposited in soft tissues during prolonged DOX infusions without producing severe acute symptomatology. Furthermore, an analysis of DOX content in excised tissues may help guide the surgical management of the patient experiencing an extravasation.

Arm↗
PubMed1989

Association of lysosomal activity with sensitivity and resistance to tumor necrosis factor in murine L929 cells.

The cytotoxic mechanism of action of tumor necrosis factor (TNF) was examined using murine L929 fibrosarcoma cells in vitro. Two cell lines were evaluated: parental TNF sensitive (L929S) (50% cytotoxic concentration, 2-6 ng/ml); and TNF resistant (L929R) (50% cytotoxic concentration, greater than 10,000 ng/ml). The latter resistant cell line was developed by serial passage in increasing concentrations of recombinant human TNF. Sensitive cells demonstrated cytolytic and cytostatic effects at TNF concentrations between 2 and 6 ng/ml, respectively. However, TNF failed to show any selective depression of RNA, DNA, or protein synthesis or ATP content in these cells until general cell death was apparent, as defined by the cell rounding and lifting off the plastic surface. The cytokine also failed to cause DNA single-strand breaks, as detected by alkaline elution techniques. TNF was also found to be no more active in glutathione-depleted cells than in target cells containing normal glutathione levels. In contrast, various nonspecific lysosomotropic agents such as ammonium chloride and D-saccharic acid lactone led to a marked inhibition of the cytotoxic action of TNF in vitro. Furthermore, significant differences in lysosomal enzyme activity were noted between L929S and L929R cells. The changes in L929R cells involved a 50% reduction in total lysosomal protein levels and a marked depression of beta-glucuronidase activity. In contrast, L929R lysosomal hexosaminidase activity was significantly elevated over the L929S cells. From these studies it is concluded that the antitumor activity of TNF does not involve specific inhibition of macromolecular synthesis, ATP production, or the level of reduced thiols. Instead, TNF cytotoxicity appears to require functional lysosomes, which are altered when TNF resistance develops in vitro.

Adenosine Triphosphate↗
PubMed1989

Role of glutathione and its associated enzymes in multidrug-resistant human myeloma cells.

Multidrug resistance (MDR) is a phenomenon associated with the emergence of simultaneous cross-resistance to the cytotoxic action of a wide variety of structurally and functionally unrelated antineoplastic agents. The present study was undertaken to determine if 8226 human myeloma cells possessing the MDR phenotype had an increased ability to resist the intercalating drug doxorubicin (DOX) via glutathione-based detoxification systems. Glutathione S-transferase (GST) was isolated by affinity chromatography, and the enzyme activity was assessed using 1-chloro-2,4-dinitrobenzene (CDNB) and glutathione (GSH) as substrates. There was no difference in overall GST activity between the sensitive and resistant cells. Using a cDNA probe (pGTSS1-2) for the human placental, anionic GST isoenzyme, no overexpression of mRNA for this isoenzyme was noted in the resistant line. When glutathione peroxidase activity (GSH-px) was assessed using either H2O2 or cumene hydroperoxide as substrate, again there was no difference in enzyme activity. Non-protein sulfhydryl (NPSH) levels were found to be elevated significantly in the resistant 8226/DOX40 subline (19.2 +/- 0.1 nmol NPSH/10(6) cells) as compared to the drug-sensitive parental subline 8226/S (11.6 +/- 1.9 nmol NPSH/10(6) cells) (P less than 0.001). In addition, when the 8226/DOX40 cells were cultured in medium without doxorubicin, there was a consistent decline in NPSH values reaching a steady state identical to that of the 8226/S cells. However, the decrease in NPSH level was not accompanied by a change in the level of doxorubicin resistance as assessed by colony-forming assays. Depletion of glutathione by D,L-buthionine-S,R-sulfoximine had no effect on doxorubicin sensitivity in either subline. Thus, it appears that GSH-based detoxification systems are not causally involved in maintaining the MDR phenotype in 8226 human myeloma cells; rather they appear to comprise an epiphenomenon associated with the resistance selection procedure.

Buthionine Sulfoximine↗
PubMed1989

Antitumor activity and murine pharmacokinetics of parenteral acronycine.

The lipophilic antitumor alkaloid acronycine (ACRO) was solubilized in the cosolvent system used for etoposide. ACRO in this etoposide diluent (VPD) was found to be cytotoxic (less than or equal to 50% colony formation in soft agar) in fresh human tumors from patients with renal cell cancer, ovarian cancer, uterine cancer, and metastatic tumors of unknown primary. In P-glycoprotein-positive, multidrug-resistant (MDR) cell lines, ACRO in VPD was active in MDR Chinese hamster ovary cells but not against MDR L1210 murine leukemia cells, 8226 human myeloma cells, or human CCRF-CEM lymphoblasts. In mice, ACRO in VPD was active in two solid tumor models and an i.p. MOPC-315 plasmacytoma model. ACRO i.p. in 10% VPD (v/v%) produced significant tumor growth delays in (a) nude mice bearing human MCF-7 breast cancer xenografts and (b) C57BL mice bearing colon 38 tumor. In MOPC-315-bearing mice, a single i.p. ACRO dose of 25 mg/kg was as effective as melphalan (15 mg/kg) at prolonging life span. Finally, ACRO pharmacokinetics was evaluated in mice given single 25-mg/kg doses i.p. or p.o. The oral bioavailability of an ACRO solution in VPD was only 50% but both i.p. and p.o. regimens achieved plasma levels greater than 1.0 micrograms/ml. The plasma half-life was just under 2 h. These results show that parenteral ACRO in VPD comprises a cytotoxic antitumor agent with improved bioavailability over p.o. administration. ACRO is active in vitro against several human solid tumors but is cross-resistant in 3 of 4 MDR tumor cell lines. The prior clinical activity of p.o. ACRO in myeloma and the new results in MOPC-315 plasmacytomas in mice suggest that ACRO in VPD could have activity against human multiple myeloma.

Acronine↗
PubMed1989

Alpha-globulins suppress human leukocyte tumor necrosis factor secretion.

The secretion of tumor necrosis factor (TNF) by human peripheral blood mononuclear cells was suppressed by either whole human plasma alpha-globulins or purified alpha 1-acid-glycoprotein, alpha 1-antitrypsin and alpha 2-macroglobulin in a concentration-dependent manner. alpha 1-Antitrypsin was found to be the most suppressive of the purified proteins tested and completely blocked TNF release at concentrations above 1.25 mg/ml. Both alpha 1-acid glycoprotein and alpha 1-antitrypsin blocked TNF secretion by leukocytes which were simultaneously stimulated with either recombinant human interferon-gamma (IFN-gamma) or lipopolysaccharide (LPS). IFN-gamma- and LPS-activated cells were also susceptible to suppression mediated by these two alpha-globulins and the inhibition produced by 5 mg/ml alpha 1-antitrypsin was greater than that caused by either 1 microM prostaglandin E2 or 10 ng/ml transforming growth factor-beta 1. The level of TNF mRNA in TNF-secreting and alpha-globulin-suppressed cells was examined and found to be equal in both groups. The suppressive effect of whole alpha-globulins was confined to the inhibition of TNF secretion and these plasma proteins had no effect on the cytolytic activity of the recombinant cytokine as measured on murine L-929 target cells. Thus the alpha-globulins, which are a major fraction of the circulating plasma proteins, may function in TNF homeostasis by controlling TNF secretion without inhibiting the biological activity of the released cytokine.

Adult↗
PubMed1989

Interaction between cisplatin and mesna in mice.

The uroprotectant thiol mesna was found to protect adult CD-1 mice from high-dose cisplatin lethality. Mesna doses of 50 mg/kg were given with cisplatin, or 5 min after cisplatin (25 or 30 mg/kg) and acute survival was increased in non-tumor-bearing mice. In contrast, mesna mixed directly with cisplatin significantly reduced cisplatin antitumor effects in DBA/2J mice given 10(6) P-388 leukemia i.p. Mesna administered i.p. 5 min after cisplatin (6, 8 or 10 mg/kg) did not reduce cisplatins' antitumor efficacy in this same tumor model. Mesna appears to inactivate cisplatin directly in vitro but possibly not in vivo if separate injections are used.

Animals↗
PubMed1989

H2-antagonists and carmustine.

The highly metabolized nitrosourea carmustine (BCNU) is an anticancer agent which alkylates DNA and is metabolized to both active and inactive species by cytochrome P-450 enzymes. Other highly metabolized anticancer drugs have altered toxicities when some histamine H2 antagonists are coadministered. To test this hypothesis with BCNU, DBA/2J male mice were given a single injection of cimetidine (CMT 100 mg/kg) or ranitidine (RNT 25 mg) at various times up to 30 min before, or up to 60 min after a BCNU injection. Spleen colony assays for normal bone marrow stem cell viability showed enhanced toxicity for BCNU when CMT was administered concomitantly. In P-388 leukemia-bearing DBA/2J mice, both CMT and RNT significantly enhanced the antitumor effects of BCNU doses of 30 mg/kg. Pharmacokinetic analyses of BCNU elimination in Cd-1 mice showed marked prolongation of BCNU elimination and increased (BCNU concentration) x time products when CMT was concomitantly administered. These results demonstrate that enhanced BCNU bone marrow toxicity and antitumor activity is produced by CMT. The effect appears to be related to impaired drug clearance when the two agents are administered concurrently. RNT slightly enhanced BCNU antileukemic effects, but it did not significantly alter BCNU myelotoxicity nor drug elimination patterns.

Animals↗