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Biomedical subjects

A Goldin

Publications and source records attributed to A Goldin.

At least 37 records · Page 2Linked to original sources
PubMed1981

Combined effects of natural resistance and chemotherapy against a murine lymphoma in lethally-irradiated mice.

Lymphoma EL-4 of B6 origin was inoculated into lethally-irradiated syngeneic B6 or resistant BD2F1 hybrid recipients. Marked impairment of lymphoma cell proliferation (i.e. hybrid resistance, HR) occurred in the spleen but not in the liver or lung of BD2F1 hosts. Treatment with DTIC at the optimal dose of 80 mg/kg i.p. produced inhibitory effects in spleen, liver and lung of young BD2F1 mice, that were much greater than those observed in syngeneic B6 hosts. Increased anti-lymphoma effects for HR and DTIC chemotherapy were not detectable in the liver or lung of old BD2F1 mice or in the spleen, liver or lung of young hybrid recipients depressed for HR by pretreatment with cyclophosphamide. This is the first report on combined antileukemic effects of the host's anti-tumor natural resistance and chemotherapy.

Animals↗
PubMed1981

Chemotherapy of human colorectal tumor xenografts in athymic mice with clinically active drugs: 5-fluorouracil and 1-3-bis-(-2-chloroethyl)-1-nitrosourea (BCNU). Comparison with doxorubicin derivatives: 4'deoxydoxorubicin and 4'-O-methyldoxorubicin.

The effects of single-agent therapy with two clinically useful drugs, 5-fluorouracil (5-FU) and 1-3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) against nine human colorectal tumors (rectum T 157 and T 348, lung metastasis T 84, lymph-node metastasis T 245, colon, T 183, T 219, T 347, T 362 and T 380) transplanted and passed serially in thymic (nude) mice were studied. In addition, chemosensitivity of the tumors to 5-FU and BCNU was compared with the chemosensitivity of the tumors to two new doxorubicin analogues, 4'-deoxydoxorubicin and 4'-0-methyldoxorubicin. BALB/c nude mice were treated intravenously on a weekly basis for 3-4 weeks, starting when the tumor volume became relatively large (advanced stage of tumor treatment). All the tumors showed a 90-100% take rate and stable growth. In these experiments, 77% (5/9) of the colorectal tumors were biologically sensitive to the treatment with 5-FU but the percentage of statistically significant sensitive tumors was 22%, which is in good agreement with the clinical data reported in the literature (21%). In patients, BCNU has been reported to give up to 13% response. In contrast, we have found a 33% statistically significant response rate in our panel of colorectal tumors. The difference could be related to the higher tolerance of nude mice to certain drugs, including BCNU. The results suggest that the two new doxorubicin derivatives, 4'-deoxydoxorubicin and 4'-0-methyldoxorubicin, should be more active in the patient than both of the clinically used drugs, 5-FU and BCNU. Furthermore, there is a good correlation between the results obtained in the experimental system (human tumor/nude mouse) and in human patients with the active drugs, 5-FU and BCNU.

Adenocarcinoma↗
PubMed1981

Transplantation resistance of drug-treated allogeneic mice against murine lymphomas--II. Studies with various tumor-host combinations.

Previous studies showed that treatment of mice with 5(3,3'-dimethyl-1-triazeno)-amidazole-4-carboxamide (DTIC) plus cyclophosphamide (Cy) produce profound depression of classical allograft responses and impairment of endogenous cell proliferation similar to that detectable in lethally-irradiated mice. However efficient localized graft resistance was found in the spleen of drug-treated hybrid or allogeneic mice challenged with lymphoma cells. The present report describes the genetic patterns of this type of natural resistance [hereafter called drug-resistant inhibition of tumors (DRIT) in various tumor-host combinations DRIT was evaluated measuring the extent of 125I-5-iodo-2'-deoxyuridine (125IUdR) uptake in the spleen and liver of leukemic hosts. The results of the experiments performed with two H-2d (i.e. L1210 and LSTRA), one H-2b (i.e. L5MF-22) and one H-2a (i.e. LAF-17) lymphomas inoculated into drug-treated recipients pointed out that: (a) tumor cell proliferation was markedly inhibited in the spleen and weakly or not impaired in the liver of D end Hh-1-incompatible euthymic or nude mice responder for the hh system; (b) no resistance was found in the spleen and liver of Hh-1-compatible B10.A (2R) mice against L5MF-22 lymphoma or of SJL recipients genetically non-responder for the Hh system, against LSTRA cells; (c) splenic resistance against L1210 leukemia was detectable in Hh-compatible B10.A or B10.A (5R) mice; (d) splenic and liver resistance was found in Hh-incompatible but genetically Hh non-responder SJL or C3H mice against L5MF-22 or LSTRA lymphomas, respectively. These results showed that the genetic patterns of the DRIT system parallels the Hh-type immunity in certain tumor-host combinations [(a) and (b)] but not in others [(a) and (d)], as previously detected in lethally-irradiated mice. It is concluded that genetically-controlled lymphoma graft resistance can be retained by mice treated with high doses of antitumor drugs, capable of abrogating classical T-dependent transplantation immunity.

Animals↗
PubMed1981

Animal toxicology for early clinical trials with anticancer agents.

This analysis was carried out to assess quantitative and qualitative relationships between animal and human toxicology data with anticancer drugs. Among 21 chemotherapeutic agents, one-sixth LD10 in the mouse or one-third toxic dose low (TDL) in the dog corresponded to acceptable doses in man when experimental and clinical data were obtained at identical schedules and compared on a mg/m2 basis. The mouse and the dog largely differed in their tolerance to individual drugs. One-tenth LD10 in the mouse seemed always tolerated in the dog. On the average, these species were equally relevant for establishing the initial dose in man. A similar number of dose escalation steps would have been required in phase I clinical trials if the starting dose had been based on one-tenth LD10 in the mouse or the lowest value of one-sixth LD10 in the mouse and one-third TDL in the dog. These observations indicate that the starting dose in phase I clinical trials could be safely and efficiently based on one-tenth LD10 in the mouse. Prior verification that the resulting dose is not lethal or life-threatening in the dog could add further safety to this procedure. The predictive value (PV+) in man of organ system toxicity in animals depends upon the prevalence of this toxicity in man. In our study, PV+ was high (greater than 0.85) for common toxic effects in man, i.e., gastrointestinal intolerance and myelosuppression. PV+ declined dramatically (0.05 to 0.54) with rarer toxic manifestations. There was no clear superiority of animal findings over the mere knowledge of the prevalence of these findings in man. Thus, it would appear that routine and undiscerned investigation of organ system toxicity in animals is of questionable usefulness for the clinician experienced in early clinical trials with chemotherapeutic agents.

Animals↗
PubMed1981

Chemotherapy and immunotherapy of L1210 leukemic mice with antigenic tumor sublines.

Tumor cells, treated in vivo with anticancer compounds, may acquire new antigenic specificities in addition to any original antigens associated with parental tumors. Treatment of mice carrying the parental leukemias L1210 Ha or L1210 Cr with leukemia cells antigenically altered by treatment with 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (L1210 Ha/DTIC and L1210 Cr/DTIC, respectively) was essentially ineffective in prolonging the life span of the animals. However, synergic therapeutic activity was exhibited by administration of L1210 Ha/DTIC cells plus 1,3-bis(2-chloroethyl)-1-nitrosourea in the treatment of the moderately immunogenic L1210 Ha leukemia and by the combination of L1210 Cr/DTIC cells and lymphocytes immune to L1210 Cr/DTIC administered with 1,3-lymphocytes immune to L1210 Cr/DTIC administered with 1,3-bis(2-chloroethyl)-1-nitrosourea in the treatment of the low immunogenic L1210 Cr leukemia. Early and advanced L1210 Cr-bearing mice showed marked increases in survival time and a significant number of tumor-free survivors on treatment with cyclophosphamide followed by transfer of lymphocytes immune to L1210 Cr/DTIC cells. When parental tumor cells were used as the immunogen, the therapeutic effect was diminished. Thus, in the current investigation, although immunotherapy per se was essentially ineffective, the immunochemotherapeutic modalities used were successful in markedly increasing the survival time of leukemic animals and resulted in an incidence of cures.

Animals↗
PubMed1981

In vitro generation of a highly immunogenic subline of L1210 leukemia following exposure to 5-(3,3'-dimethyl-1-triazeno)imidazole-4-carboxamide.

Strong and heritable increase of immunogenicity of L1210 Ha leukemia has been obtained in vitro following multiple treatments with 5-(3,3'-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC), metabolically activated by mouse liver preparations (MLP) containing liver microsomes. The DTIC-treated leukemia (L1210D line) or the control line treated with MLP alone (L1210N line) showed comparable growth kinetics in vitro. However, progressive increase of immunogenicity occurred in leukemic cells in the course of in vitro treatments with DTIC plus MIP, but not with MLP alone, as evidenced by comparative studies on transplantation immunity elicited in BALB/c x DBA/2 F1 mice by graded inocula of L1210D or L1210N leukemia cells. In vitro experiments confirmed that metabolic transformation of DTIC is required for increasing tumor immunogenicity. In fact, L1210Ha cells became highly immunogenic when treated with DTIC in intact mice but not in animals metabolically depressed by CCl4. Immunochemotherapy experiments based on the antigenic cross-reactivity between the L1210D line and the original L1210Ha leukemia showed that i.p. administration of L1210D cells followed by 1,3-bis(2-chloroethyl)-1-nitrosourea treatment afforded marked protection in mice inoculated intracerebrally with the parental lymphoma. The present findings could provide an adequate in vitro technique for developing further studies on DTIC-mediated immunogenic changes of tumors, including human cancer cells growing in tissue culture.

Animals↗
PubMed1981

Clinical concepts derived from animal chemotherapy studies.

Animal chemotherapy studies have contributed significantly to clinical concepts in tumor therapy. Preclinical investigations have led to the discovery of new drugs and have demonstrated that it is possible to cure advanced metastatic neoplasia. A fundamental clinical concept stemming from animal chemotherapy studies is that increased selectivity and improved therapeutic effectiveness of antitumor agents may result from appropriate pharmacologic, biochemical, and biologic manipulation of the host-tumor drug relationship. Clinically important factors that may increase antitumor drug selectivity are reviewed and pertinent studies in animal model systems are cited.

Animals↗
PubMed1981

Drug-mediated increase of tumor immunogenicity in vivo for a new approach to experimental cancer immunotherapy.

In vivo treatment of leukemic mice with the antitumor agent 5-(3,3'-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) results in early increase of tumor-associated immunogenicity which is expected to evoke host-versus-graft responses. However, transplantation immunity is severely impaired in DTIC-treated mice due to the immunodepressant activity of the drug. It follows that the DTIC-mediated increase of tumor immunogenicity effect cannot be of therapeutic value in ordinary conditions. In the present report, we describe the results of studies aimed at restoring immunocompetence of DTIC-treated mice by means of adoptive transfer of syngeneic lymphoid cells. Infusion of spleen cells into DTIC-treated mice failed to restore graft responsiveness even in allogeneic tumor-host combinations. However, when DTIC treatment was followed by administration of cytotoxic alkylating agents such as cyclophosphamide (CY) or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), graft responsiveness was partially restored upon adoptive transfer of syngeneic splenocytes. (BALB/c X DBA/2) F1 (hereafter called CD2F1) mice bearing leukemia L1210 Ha were treated as follows: (a) DTIC for increasing the immunogenicity of the leukemic cells; (b) CY or BCNU; and (c) adoptive transfer of CD2F1 lymphocytes. The results showed that: (a) DTIC alone or DTIC plus spleen cells produced little or no increase in survival times with respect to untreated controls; (b) DTIC plus CY or BCNU increased survival times to a larger extent; and (c) the adoptive transfer of lymphocytes produced marked protection of leukemic mice when the hosts had been pretreated with DTIC plus CY or BCNU but not with CY or BCNU without DTIC. These data may provide a model for exploiting DTIC-induced increase of tumor immunogenicity for immunochemotherapeutic regimens.

Animals↗
PubMed1980

Transplantation resistance of drug-treated hybrid or allogeneic mice against murine lymphomas. I. Immunopharmacology studies.

Sequential treatment of mice with non-lethal doses of 5(3,3'-dimethyl-l-triazeno)-imidazole-4-carboxamide (DTIC) and cyclophosphamide (Cy) was found to produce long-term inhibition of endogenous cell proliferation in the spleen and profound impairment of classical allograft responses, similar to that detectable in lethally irradiated mice. Studies were carried out with drug-treated (i.e. treated with DTIC + Cy) conventional or nude mice inoculated with lymphoma cells homozygous for the H-2b or H-2d haplotype. Transplantation resistance in various tumour-host combinations was studied in terms of survival times after tumor challenge or lymphoma cell proliferation in spleen and liver, measured by the uptake of DNA precursor 125I-labelled 5-iodo-2'-deoxyuridine ([125I]dUrd). The results of in vivo transplantation immunity tests or in vitro tests of generation of cytotoxic lymphocytes confirmed that classical T-dependent allograft responses were abrogated by drug treatment of H-2-incompatible hosts. However, localized resistance against lymphoma graft, mainly at spleen level, was found in drug-treated hybrid mice, or conventional and "nude" allogeneic recipients, as judged by [123I]dUrd uptake inhibition. Resistance presumably regulated, at least in part by the Hh (hemopoietic histocompatibility) system, was abrogated by pretreatment with carrageenan, an antimacrophage agent. In addition, treatment with DTIC + Cy did not abrogate NK activity of mice when the in vitro cytotoxicity test was conducted 5 h after Cy administration, i.e. at the time used for tumor challenge in vivo. It was concluded that selected immunological functions (i.e., antilymphoma natural resistance insensitive to DTIC + Cy, called drug-resistant inhibition of tumors, DRIT) possibly of non-T origin, similar to those detectable in lethally-irradiated mice, can be retained by hosts subjected to high doses of certain anti-tumor agents.

Animals↗
PubMed1980

Chemotherapy immunogenicity.

A number of studies have demonstrated that a moderate immune reaction may augment the response to chemotherapy. Two approaches are examined in the current report: (a) chemoimmunotherapy with viable L1210 cells that were antigenically altered by treatment with DTIC (L1210/DTCI), and (b) chemotherapy plus treatment with lymphocytes from mice immunized against L1210/DTCI. Treatment of the parental leukemias L1210 Ha and L1210 Cr with BCNU or cyclophosphamide in combination with viable antigenically altered tumor cells and with lymphocytes immunized against the antigenically altered tumor cells resulted in marked therapeutic responses. The observations suggest that these combined therapeutic modalities are worthy of investigation employing human tumors.

Animals↗