Biomedical subjects

M J Soble

Publications and source records attributed to M J Soble.

8 recordsLinked to original sources

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↗

PubMed1988

Cimetidine enhances cisplatin toxicity in mice.

The combination of the histamine H2 antagonist cimetidine (CMT) and the anticancer agent cisplatin (CDDP) was studied in normal and tumorbearing mice. CMT doses of 100 mg/kg produced no alteration in the survival of DBA/2J mice bearing P388 leukemia treated with CDDP doses of 3 mg/kg or 6 mg/kg. In these groups, the median survival was 13 days and 16 days, respectively, compared to 10 days in untreated controls. However, when adult CD-1 mice were given higher but nonlethal CDDP doses of 10, 15, or 18 mg/kg, the addition of CMT significantly increased CDDP lethality (P less than 0.05 by Wilcoxon analysis). For the 3 groups, CMT-enhanced lethality occurred in 10% of mice given 10 mg/kg CDDP, 80% of mice given 15 mg/kg, and 100% of mice given 18 mg/kg CDDP. Thus, CMT can acutely alter CDDP toxicity without affecting antitumor efficacy in mice.

Animals↗

PubMed1987

Dose-dependent skin ulcers in mice treated with DNA binding antitumor antibiotics.

The DNA-binding agents daunomycin (DAU-NO), mithramycin (MITH), dactinomycin (ACT-D), amsacrine (mAMSA) and esorubicin (ESO) were tested for local vesicant potential in a quantitative intradermal mouse skin model. Only MITH, which adlineates but doses not intercalate DNA, did not produce dose-dependent skin ulcerations in the mouse. The anthracycline antibiotics DAUNO and ESO produced the largest skin ulcers when administered intradermally at clinically relevant doses (adjusted on the basis of comparable body surface areas). Numerous local pharmacologic adjuvants were tested for activity to decrease skin ulceration patterns in mice given one of the DNA intercalators. Inactive local adjuvants included heat, cold, saline, hyaluronidase, glucorticosteroids and isoproternol. Only one adjuvant, topical dimethylsulfoxide (DMSO), was found to reduce DAUNO skin lesions. A single topical DMSO application significantly decreased ulceration size to almost half of control levels. However, it was ineffective for the other intercalating agents. These results show that the DNA intercalators DAUNO, ESO and ACT-D are potent vesicants in a mammalian skin model. These vesicant agents must be administered cautiously to prevent extravasation. No single local adjuvant treatment can be recommended for extravasation of these drugs in the clinic. One significant exception is DAUNO, where topical DMSO may reduce clinical toxicities.

Adjuvants, Pharmaceutic↗

PubMed1987

Lack of enhanced myelotoxicity with buthionine sulfoximine and sulfhydryl-dependent anticancer agents in mice.

The lethal and non-lethal effects of L-buthionine-SR-Sulfoximine (BSO) with the sulfhydryl-dependent anticancer agents (SHDAA) were investigated in mice. The agents studied included carmustine (BCNU), cyclophosphamide (CTX), doxorubicin (DOX) and melphalan (LPAM). It was shown in normal mice that BSO is nontoxic when given IP or PO at a dose 5 g/kg. In pharmacodynamic studies with two different doses of BSO in CD-1 mice, the liver, kidney and heart demonstrated diurnal variations in thiol content and dose-dependent depression of tissue non-protein sulfhydryl (NPSH) levels. In acute lethal survival studies, mice treated with CTX and BSO exhibited increased lethality with seizures as a possible cause of death. This effect was not seen with BCNU, DOX and LPAM. Evaluations of organ-specific biochemical markers, showed slight elevations in LDH enzyme levels while bone marrow suppression was not enhanced using both in vivo spleen colony assay and in vitro colony forming unit myelotoxicity assays. These results show that the addition of BSO with SHDAA enhances the acute lethality of some agents such as CTX, and may also increase the non-myelosuppressive toxicities of other agents. It is recommended that BSO be used with caution in combination with SHDAA and that monitoring of hepatic enzymes be routinely performed.

Animals↗

PubMed1986

Cytotoxic effects of glutathione synthesis inhibition by L-buthionine-(SR)-sulfoximine on human and murine tumor cells.

The glutathione (GSH) synthesis inhibitor, buthionine sulfoximine (BSO) was tested for cytotoxicity and thiol depletion in murine and human tumor cells in vitro, and for its antitumor activity and toxicity in vivo. The cell lines used in these studies included murine L-1210 leukemia, human RPMI 8226 myeloma, MCF-7 breast cancer and WiDr colon carcinoma. Soft agar colony forming assays showed that BSO was most effective at reducing tumor colony formation when exposed continuously to cells in vitro. Drug concentrations which inhibited colony formation to 50% of control levels ranged from 2.0-6.2 mM (for 1 hour exposures), 2-100 mM for 24 hour exposures and 0.4-1.40 microM (for continuous BSO exposures). Human myeloma cells proved most sensitive to BSO. In vitro cytotoxicity correlated with depletion of intracellular nonprotein sulfhydryls to less than or equal to 10% of control values in both L-1210 and 8226 cells. This was routinely achieved with prolonged exposures to mM BSO concentrations for greater than 24 hours. Normal mice tolerated high BSO doses (up to 5.0 g/kg) without evidence of acute toxicity. BSO was not active against L-1210 leukemia-bearing DBA/2 mice. When tested in vivo against MOPC-315 plasmacytoma-bearing BALB/c mice, BSO was not active at doses up to 4.0 g/kg. In contrast, the bifunctional alkylating agent melphalan (L-PAM) was active against MOPC-315 and this activity was enhanced by a 24 hour pretreatment of mice with 50 mg/kg of L-BSO.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Mitomycin C skin toxicity studies in mice: reduced ulceration and altered pharmacokinetics with topical dimethyl sulfoxide.

A series of toxicologic and pharmacokinetic studies were performed in BALB/c mice administered intradermal (ID) mitomycin C (MMC) at doses of .015 to 0.25 mg. Dose-dependent skin ulcers were produced at clinically relevant MMC dose levels of .05 and .075 mg (3.6 to 10.7 mg/m2). These doses produced peak ulcers of 0.15 to 0.22 cm2, respectively, one to five days after injection. The integrated ulcer area X time values (area under the curve [AUC] ulceration) were 0.89 and 3.11 cm2 X d. A large number of local pharmacologic adjuvants were found to be ineffective at reducing MMC ulceration after proximal ID injection. These included diphenhydramine, catalase, heparin, hyaluronidase, hydrocortisone, cysteine, N-acetylcysteine, lidocaine, vitamin E, and superoxide dismutase. Also, neither topical heating nor cooling of skin reduced MMC ulcerations. In contrast, a single topical application of a 100% dimethyl sulfoxide (DMSO) solution completely prevented 0.025 mg MMC-induced skin ulceration and significantly reduced .075 mg MMC ulceration (P less than .05 by multiple range tests). Topical DMSO also altered the disposition of ID MMC in mouse skin but not in plasma. Unexpectedly, the DMSO applications slowed MMC elimination from the skin. DMSO significantly increased the AUC for MMC in skin from 0.89 to 2.25 ng/h/mL of tissue (P less than .05). DMSO did not alter the degree of protein binding in skin tissue nor the in vitro chemical stability of MMC in skin tissue homogenates. These results show that experimental MMC-induced skin ulcers in mice can be ameliorated with an immediate application of topical DMSO. This effect is not due to enhanced systemic drug uptake, but may be due to reduced reactivity of MMC with target cellular nucleophiles.

Animals↗

PubMed1986

Interaction of cimetidine but not ranitidine with cyclophosphamide in mice.

A series of experiments in DBA/2J mice evaluated the biological and pharmacokinetic interactions of the alkylating agent cyclophosphamide (CTX) and the histamine-H2 antagonists cimetidine (CMT) and ranitidine (RNT). Doses were adjusted to approximate human dose levels: 100 mg/kg for CMT; and 25 mg/kg for RNT. CMT reduced the survival of normal (bone marrow stem cell) colony forming units in a dose dependent fashion. CMT, given 5 or 30 min before CTX (200 mg/kg), significantly increased the survival of leukemia bearing mice, as well as the elimination half-life and plasma area under the curve of total alkylating metabolites of CTX. RNT did not significantly alter CTX antileukemic activity, pharmacokinetics, or toxicity to normal bone marrow stem cells. These results suggest caution in the use of CMT in patients being treated with CTX in order to avoid the possibility of exaggerated CTX toxicities. RNT may comprise a safer histamine-H2 antagonist to use with CTX if a histamine-H2 antagonist is clinically indicated.

Animals↗

PubMedDate not supplied

Lack of enhanced antitumor efficacy for L-buthionine sulfoximine in combination with carmustine, cyclophosphamide, doxorubicin or melphalan in mice.

A series of studies was performed in tumor bearing mice to evaluate the impact of glutathione (GSH) depletion by L-buthionine sulfoximine (L-BSO). L-BSO doses of 50 or 500 mg/kg were used alone or with one of 4 sulfhydryl-dependent anticancer agents (SHDAA). When L-BSO was administered to tumor-bearing mice, Colon 38 cells were significantly depleted of GSH content, but this did not occur with P388 cells or MOPC-315 cells in vivo. GSH levels in these ascites tumors declined significantly without L-BSO treatment as the tumor rapidly grew in the IP space. SHDAAs, including doxorubicin (DOX), cyclophosphamide (CTX), carmustine (BCNU) and melphalan (L-PAM) were then combined with L-BSO in mice bearing P388, MOPC-315 or colon 38 tumors. There was no consistent enhancement of antitumor efficacy using a treatment interval of 24 hrs (L-BSO given first). In contrast, there was some evidence of significantly enhanced SHDAA toxicity with L-BSO. Further studies should evaluate different dosing intervals to take advantage of the slower rate of GSH replenishment observed in normal tissues compared to solid tumor cells (Colon 38) in vivo. In addition, significant reductions for any SHDAA combined with L-BSO are indicated in any such trial.

Animals↗