Biomedical subjects

W C Rose

Publications and source records attributed to W C Rose.

96 records · Page 6Linked to original sources

PubMedDate not supplied

Development of a human xenograft model for the evaluation of monoclonal antibody L6-mitomycin immunoconjugates.

The human lung carcinoma H2981, was characterized as a preclinical model for evaluating immunoconjugates consisting of monoclonal antibody (MAb) L6 and drugs of the mitomycin (MMC) chemotype. The H2981 tumor, implanted subcutaneously in athymic, mice grew progressively in greater than 95% of recipients. Spontaneous regressions of established tumors were not observed. The administration of tolerated doses of MMC resulted in dose-dependent delays in tumor growth. The incidence of tumor regressions was low indicating the potential to observe increased efficacy with immunoconjugates. The antitumor effects of MMC were independent of the schedule and route of administration. MAb L6 delayed the outgrowth of tumors when administered 24 h after tumor implant. Antitumor activity was not observed when MAb L6 was administered to mice bearing established tumors. The efficacy of mixtures of MAb L6 and optimal doses of MMC was not significantly better than that of optimal doses of MMC given alone.

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PubMedDate not supplied

In vivo characterization of P388 leukemia resistant to mitomycin C.

A line of P388 leukemia resistant to mitomycin C (MMC) was successfully developed in vivo by treating mice bearing parental P388 (P388/0) with MMC followed by serial passage of the surviving leukemic cells. From this P388/MMC line, a subline was derived by not treating the passage mice with MMC (P388/MMC-NP); resistance to MMC was stable for as many as 56 weeks of transplantation. The chemosensitivities of each P388 line to assorted anticancer drugs were compared in vivo. Both P388/MMC and P388/MMC-NP had similar patterns of drug cross-resistance and collateral sensitivity. With respect to alkylating agents (e.g. cyclophosphamide, Platinol and chlorambucil), there was generally a partial degree of cross-resistance, sometimes only detectable at suboptimal dose levels. With respect to DNA binders or intercalators (e.g. actinomycin D, luzopeptin A, amsacrine, doxorubicin), the extent of cross-resistance varied from none (dihydoxyanthraquinone) to marked (doxorubicin). Antimitotic inhibitors (vinblastine and vincristine) were completely cross-resistant, as were some miscellaneous natural agents (rebeccamycin, VP-16, sesbanimide, and elsamicin, a chartreusin analog). Antimetabolites (e.g. methotrexate and 6-thioguanine) showed no cross-resistance and even demonstrated some occasional evidence of collateral effectiveness.

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PubMedDate not supplied

Correlation of in vitro cytotoxicity with preclinical in vivo antitumor activity.

Several human and murine tumor cell lines were evaluated in an in vitro cytotoxicity assay as prescreens for fermentation extracts and pure materials subsequently tested in vivo against P388 leukemia or B16 melanoma. Each material, regardless of its in vitro cytotoxicity, was evaluated in vivo. At the criteria levels of in vitro positivity and in vivo activity invoked, a highly significant relationship between these two endpoints was demonstrated for each cell line. When cell lines were compared, most of them performed in a similar manner, with HCT-116 human colon carcinoma cells providing a modest advantage predicting for P388 activity in some comparisons. Using the data from any two cell lines in concert did not improve the acuity of the prescreen beyond that associated with the better cell lines used singularly and only a minority of active materials was predicted for uniquely. Overall, the in vitro cytotoxicity assay provided a useful prescreen for selecting P388 and B16 in vivo active materials.

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PubMedDate not supplied

Evaluation of platinol analogs using the M5076 murine sarcoma.

The M5076 sarcoma was used to evaluate the antitumor activities of several analogs of Platinol presently undergoing clinical trials. The objective was to find a model yielding preclinical data which correlated with evolving clinical results, and thus potentially provide a validated model for the subsequent testing of new Platinol analogs. The model found to be useful consisted of mice implanted s.c. with M5076 tumor fragments. Platinol, carboplatin, and iproplatin were consistently active (T/C values greater than or equal to 125%), whereas spiroplatin was consistently inactive. These findings reflect the clinical activities of Platinol, carboplatin, and iproplatin and the essential clinical inactivity of spiroplatin thus far reported.

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PubMedDate not supplied

Antileukemia (L1210) activity and toxicity of cis-dichlorodiammineplatinum(II) analogs.

cis-Dichlorodiammineplatinum(II) (cis-platinum) and 40 of its analogs were evaluated for antitumor activity in BDF1 mice implanted ip with 10(6) L1210 leukemia cells. Several of these analogs were also evaluated for their ability to cause elevation in BUN and to produce leukopenia in normal BDF1 mice. In 11 experiments, cis-platinum given on Day 1 or Days 1--9 after implant produced T/C (treated/control) values between 164% and 214% and 157% and 285% respectively. On the basis of single experiments, 13 analogs were judged to be comparable to cis-platinum in that they produced T/C values greater than or equal to 167% after a single dose or greater than or equal to 200% after daily doses for 9 days. These active compounds included various substituted amine derivatives of dichloroplatinum(II), malonatoplatinum(II), aquasulfatoplatinum(II), and chloroacetatoplatinum(II) and derivatives of dihydroxydichloroplatinum(IV). Twelve of these active analogs and cis-platinum were evaluated for toxicity at doses ranging from near the optimal therapeutic dose to greater than or equal to the LD50. Only five of the 12 analogs and cis-platinum caused an increase in BUN to greater than 30 mg/100 ml, while eight of the analogs produced leukopenia comparable in incidence and severity to that produced by cis-platinum.

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PubMedDate not supplied

Evaluation of Madison 109 lung carcinoma as a model for screening antitumor drugs.

The Madison 109 lung carcinoma (M109) was evaluated as a model for the screening of antitumor agents. Thirty-five drugs with established antitumor activity were assayed in mice implanted ip or sc with M109. Depending on the mode of tumor implantation, drugs representing those affecting nucleic acids (through binding, interacalating, or inducing single-strand breaks), various alkylating agents, mitotic inhibitors, antimetabolites, and immunomodulators were able either to inhibit the growth of sc M109 or to extend the lifespan of mice given M109 ip. The ip implanted tumor was, for example, markedly affected (median survival time of treated/control mice, x 100: greater than or equal to 200% with occasional cures) by doxorubicin, mitomycin C, 10-hydroxy camptothecin, and dihydroxyanthraquinone. The sc implanted tumor, however, was markedly affected (treated - control of greater than or equal to 12 days with regard to median time to grow 1-g tumors) by bleomycin and an analog, talisomycin, and by 6-thioguanine. The M109 was responsive to many different classes of clinically active agents and can serve as a useful tool in the screening of drugs with such potential. It may be particularly useful in screening analogs of camptothecins, nitrosoureas, bleomycins, and mitomycins as well as for evaluating anthraquinones, anthracyclines, mitotic inhibitors, antimetabolites, and immunomodulators.

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