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PubMedDate not supplied

In vitro drug sensitivity of tumor cells is correlated with drug-induced inhibition of DNA synthesis.

The objective of this study was to develop a rapid in vitro method for predicting the response of human tumors to anticancer drugs. In this study an attempt was made to correlate the drug effects on the relative incorporation of (3H) thymidine (ThdR) into DNA with the sensitivity of tumor cells to that drug. The results of the study indicate that following treatment of the cells with adriamycin (ADR) or 1-(2-chloroethyl)-3-(4-methyl cyclohexyl)-1 nitrosourea (MeCCNU), there was a significant inhibition of DNA synthesis in the drug-sensitive cells. However, the inhibition was relatively small in the drug-resistant cells. Following cytosine arabinoside (Ara-C) treatment, a dramatic recovery in the rate of DNA synthesis was seen in Ara-C-resistant cells but not in cells sensitive to Ara-C. Thus, the method described in this study appears to be capable of distinguishing whether a tumor cell line is sensitive or resistant to a given drug.

Animals↗
PubMed1984

[Antitumor activity of a new nitrosourea, MCNU, on a cellular morphological basis evaluated by a new in vitro antitumor sensitivity assay].

Using our new in vitro antitumor sensitivity assay, the basis of which depends on predictive analysis of morphological findings of L1210 leukemia cells under the influence of antitumor agents, 5 kinds of nitrosoureas including MCNU were comparatively tested for antitumor activity. A cell killing effect became apparent very soon under BCNU and CCNU, rather late under Methyl-CCNU and MCNU, and intermediately under ACNU. Various cellular biological effects were apparently induced in L1210 cells by MCNU and its mechanism of action seemed to be broader than that of any other members of the nitrosoureas.

Animals↗
PubMed1983

Nephrotoxicity of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) in the Fischer 344 rat.

A single s.c. injection of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU; 20-140 mg/kg) resulted in rapid decreases in renal function as well as leading to a chronic progressive nephropathy in male Fischer 344 rats. Disturbances in renal function were proportional to the dose of MeCCNU administered and included impaired tubular transport of p-aminohippuric acid, a decrease in urine concentrating ability, an increase in urine pH, polyuria, proteinuria and enzymuria. The tubular accumulation of p-aminohippuric acid by kidney slices was decreased as early as 1 hr after MeCCNU administration (100 mg/kg), was maximal within 12 hr and remained depressed for at least 28 days after a single injection of either 40 or 80 mg/kg. Changes in other measures of renal function (increased lactate dehydrogenase excretion, alkalinuria and decreased urine concentrating ability) were delayed from 1 to 6 days after MeCCNU administration and in some cases progressed in severity throughout the 28-day duration of the experiment. The delay between the first evidence of renal damage (decreased p-aminohippuric acid uptake) and the subsequent appearance of enzymuria, proteinuria, polyuria and alkalinuria appears to correspond to a similar delay between the initial insult and the eventual development of cellular necrosis and other histopathological changes. These results demonstrate that MeCCNU is a nephrotoxicant in rats and indicate that even a single acute dose may lead to chronic and irreversible effects on the kidney. The in vivo toxicity model defined herein appears to be an appropriate one for further study of the mechanism of nephrotoxicity of MeCCNU.

Animals↗
PubMed1983

Biological and biochemical effects of N-(2-chloroethyl)-N'-(trans-4-methylcyclohexyl)-N-nitrosourea on two transplantable murine colon tumors.

Other investigators have reported that transplantable murine colon Tumor 26 is more sensitive than transplantable colon Tumor 38 to treatment with N-(2-chloroethyl)-N'-(trans-4-methylcyclohexyl)-N-nitrosourea. The present report presents the results of several kinds of in vivo and in vitro experiments that were performed to compare the effects of this agent upon these two tumors or upon cultured cells derived from them. In the in vivo experiments, data were also obtained for the spleens, colons, and marrow of the host animals. In the in vivo experiments, it was observed that: (a) approximately equal quantities of 14C from the 2-chloroethyl-14C-labeled agent were fixed to the DNA of the two tumors and the three host tissues following a single i.p. injection of the radioactive agent; (b) in all of the tissues examined at 24 hr after treatment, the drug caused greater inhibition of the synthesis of DNA than of the synthesis of RNA or protein, and the extents of inhibition of DNA synthesis were greater at 24 hr after treatment than at 6 hr after treatment; (c) the inhibition of DNA synthesis was slightly greater for Tumor 26 than for Tumor 38; (d) although the extents of inhibition of synthesis of DNA by Tumor 26 and by the colonic mucosa were similar at 24 hr after treatment of the animal, colonic mucosa much more quickly recovered the ability to synthesize DNA; and (e) the agent had no significant effect upon the sizes of the pools of purine and pyrimidine ribonucleoside phosphates. Cultured cells derived from the two tumors retained their tumorigenicity upon reimplantation into mice and their differential sensitivities to the agent, although approximately equal quantities of the 14C of the radioactive agent were fixed to the nuclei of the cells. In the in vitro experiments, the main effect of the agent upon the synthesis of macromolecules was the delayed inhibition of synthesis of DNA by Tumor 26 cells. Several experimental methods yielded evidence that the agent caused strand scission of the DNA of both kinds of cells, and there was more evidence of cross-linking of the DNA of Tumor 26 cells than of Tumor 38 cells. These results are consistent with the possibility that the differences in sensitivity of the two tumors to the agent are due to differences in the extents of cross-linking of the DNA. This explanation would be in agreement with the proposal suggested by other investigators who worked with other experimental systems.

Animals↗
PubMed1978

Sensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea of the EMT6 tumor in vivo as determined by both tumor volume response and in vitro plating assay.

Measurements of the response of the EMT6 mouse tumor to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea by either tumor volume or the in vitro assay of the cell surviving fraction give very different results. For BCNU very little delay in tumor growth is caused by high doses of the drug, whereas the surviving fraction assayed 2 hr after drug administration may be as low as 10(-4) for comparable drug doses. Over the first 48 hr after BCNU, the measured surviving fraction in small tumors increases 50- to 100-fold; this is ascribed to the phenomenon known as "recovery from potentially lethal damage." For 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, however, this early rapid recovery in surviving fraction does not occur. Although the surviving fractions measured 24 hr after drug administration are similar for equivalent doses of the two drugs, the growth delay induced is very much longer for 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea than for BCNU. Neither of the agents appears to cause any increase in the rate of cell loss from tumors as measured by [125]iododeoxyuridine.

Animals↗
PubMed1978

DNA cross-linking by in vivo treatment with 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea of sensitive and resistant human colon carcinoma xenograms in nude mice.

The DNA alkaline elution technique provides a sensitive assay for the effects of DNA-damaging drugs in mammalian cells. We have adapted this method to permit measurements of effects on DNA in solid tumors. Human colon carcinoma xenografts in nude mice were treated with a single i.p. injection of 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, and the effects on the DNA were followed for 19 hr. Drug doses in the pharmacological range produced significant reductions in DNA alkaline elution rates in assays in which X-ray was used to introduce a standard frequency of single-strand breaks. These changes in alkaline elution rate were attribute to the production of both DNA interstrand and DNA-protein cross-links, which were distinguished from each other on the basis of the extent to which the effect on elution could be reversed by proteinase K. Crosslinking increased for about 8 hr after treatment with little change thereafter up to 19 hr. A drug-resistant tumor line exhibited substantially less cross-linking than did a drug-sensitive line at all time points examined.

Alkalies↗
PubMed1978

Cancer chemotherapy model using autochthonous large bowel cancer in rats.

Chemotherapy of methylnitrosourea-induced autochthonous large bowel cancer in rats, which is similar to that in man, was studied to evaluate the intrarectal administration or topical application of chemotherapeutic agents. Rats with large bowel tumors confirmed by endoscopic examination received an intrarectal instillation of 1 mg of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), 1 mg of 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (Me-CCNU), or 5 mg of 5-fluorouracil (ir groups), or intraperitoneal injection of 2.5 mg of 5-fluorouracil (ip group) daily for 8 weeks. All the rats, including non-treated control rats, were necropsied after the treatment. The number of large bowel tumors per rat detected by endoscopy before the treatment was mostly the same among groups, whereas that observed at necropsy after the treatment was significantly smaller in ir groups, compared to non-treated group and ip group. The tumors increased significantly in rats of non-treated group and ip group between the time of endoscopy and necropsy, but not in rats of ir groups. These results showed that the maximum tolerated dosage of the agents administered intrarectally suppressed the development of new tumors after start of the treatment and also the growth of tumors which were detected by endoscopy before the treatment.

Administration, Topical↗
PubMed1982

Current management of advanced and locally unresectable gastric carcinoma.

Gastric cancer is the most chemotherapy-responsive adenocarcinoma of the major gastrointestinal sites. For patients with advanced disease, the response rates and survival achieved with recently designed Adriamycin-based regimens represent an improvement over the past use of 5-fluourouracil alone or combined with a chloroethylnitrosourea. Effective palliative treatment can be administered in an out-patient setting without the necessity of producing severe or life-threatening toxicity. Nevertheless, response durations are finite, as is patient survival. It is essential that Phase II trials of new drugs be continued in an attempt to identify agents with greater therapeutic activity for this disease. For the locally unresectable stage, combined modality therapy incorporating palliative resection of the primary tumor, regional radiation therapy and chemotherapy, has provided long-term disease-free survival for 15--25% of all patients. The most promising aspect of current clinical investigation is the application of the Adriamycin-based drug combinations in controlled trials of surgical adjuvant therapy.

Antineoplastic Agents↗
PubMedDate not supplied

Combination chemotherapy with cyclophosphamide, vincristine, methyl-CCNU, and bleomycin in advanced bronchogenic carcinoma: experience with 106 patients.

A phase II study was conducted with three different combinations of cyclophosphamide, Oncovin (vincristine), methyl-CCNU, and bleomycin (COMB) in 106 patients with advanced bronchogenic carcinoma of all histologies. The response rates were 27.3% for COMB I (six of 22 patients), 18.2% for COMB II (eight of 44 patients), and 7.5% for vincristine, methyl-CCNU, and bleomycin (three of 40 patients). Complete responses were seen only in the small cell carcinoma group. Duration of remission and overall survival were of significance for the small cell group, whereas survival for the other histologic types comparing responders to nonresponders was of no statistical significance. Toxicity was significant and included nausea and vomiting, neuropathy, and myelosuppression. These drug combinations were disappointing and only in small cell carcinoma was meaningful antitumor activity seen.

Antineoplastic Agents↗
PubMed1982

[Chemotherapy of stomach cancer].

In recent years several studies have been performed to improve the chemotherapy of metastatic gastric carcinoma. It is now established that combined chemotherapy for example with 5-Fluorouracil, adriamycin and mitomycin C or nitrosourea derivatives is superior to monotherapy with 5-Fluorouracil. With this combined chemotherapy, response rates of 30-40% can be achieved with prolonged medium survival time in responders. In locally advanced tumors the combined use of radiation and chemotherapy probably will be able to improve the results. Future studies are needed to show the role of adjuvant chemotherapy in gastric cancer patients after surgery.

Adenocarcinoma↗
PubMed1978

Phase II study of melphalan in colorectal carcinoma.

In a prospective phase II study, 25 patients with advanced (Duke's D) colorectal adenocarcinoma received 0.25 mg/kg of melphalan orally daily for 4 days every 28 days. There were 17 men and eight women. All patients had measurable areas of known malignant disease which served as objective indicators of the response to chemotherapy. All patients were evaluated for at least two cycles of therapy. Each patient had had previous treatment with 5-fluorouracil and, in addition, 24 of 25 patients had had treatment with methyl-CCNU; all patients had disease progression with both regimens. Toxicity consisted of mild gastrointestinal symptoms and transient leukopenia (wbc count less than 4000/mm3) in nine of 25 (36%) patients and thrombocytopenia (platelet count less than 100,000/mm3) in six of 25 (24%). One of 25 (4%) patients had an objective response for 12 weeks, 15 of 25 (60%) had disease progression, and nine of 25 (36%) remained stable for 2 months. We conclude that melphalan is ineffective for patients with metastatic colorectal carcinoma who have previously failed to respond to both 5-fluorouracil and methyl-CCNU.

Adenocarcinoma↗