Fine needle aspiration biopsy proves increased T-lymphocyte proliferation in tumor and decreased metastatic infiltration after treatment with doxorubicin bound to PHPMA copolymer carrier (original) (raw)
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Cancer Research, 1982
We determined that myeloma cells which survived drug treat ment had an altered sensitivity to cytotoxic antibody. The effects of several Chemotherapeutic agents differing in drug action were compared. The antiserum was directed against viral determinants on the surface of S107 myeloma cells. This antiserum was then used to inhibit the colony formation of drug-treated myeloma cells. Tumor cells were treated with melphalan (200 ng/ml), methotrexate (40 ng/ml), actinomycin D (5 ng/ml), or 0.5 HIM thymidine for 24 hr and then washed and resuspended in fresh medium. On various days after drug treatment, aliquots of these cells were exposed to complement and dilutions of antiserum and then cloned in soft agar in order to quantify the degree of antibody-mediated inhibition. Mel phalan, methotrexate, and thymidine caused a severalfold in creased resistance of the tumor cells to the antiserum during the first 1 or 2 days after drug treatment. During the following days, however, myeloma cells showed markedly increased susceptibility to the antiserum. The biphasic effect of metho trexate or thymidine treatment was similar to that previously observed after melphalan treatment and differed from the effect of actinomycin D. Actinomycin D caused only an increased susceptibility of the tumor cells to the antibody for a period of 4 to 5 days immediately following drug treatment. Our studies indicate that several Chemotherapeutic drugs at concentrations comparable to those used in humans have long-lasting antag onistic as well as synergistic effects on the sensitivity of tumor cells to antibody and complement, depending on the particular drug used and on the time interval between drug exposure and subsequent treatment with antibody. These results suggest a model for evaluating the use of antibody in the elimination of malignant cells which, despite exposure to chemotherapy, remain clonogenic and proliferative.
Studies of the mechanism of cytolysis by tumour-infiltrating lymphocytes
Clinical and Experimental Immunology, 1999
In order to determine the mechanism of tumour destruction by tumour-infiltrating lymphocytes (TIL), we examined the ability of both CD4 þ and CD8 þ effector TIL, and TIL clones, to manifest granzymemediated and Fas-mediated destruction of tumour targets. In many in vitro studies TIL have been shown to manifest anti-tumour reactivity, yet many tumours escape immunological destruction. To investigate the role of Fas expression and the concomitant sensitivity to the inducibility of apoptotic death, we derived TIL from four melanomas and one glioma. The glioma, and all but one of the melanomas, expressed Fas, but Fas-mediated apoptosis could only be detected if the targets were treated with cyclohexamide. The melanomas and the glioma all expressed detectable cytoplasmic Bcl-2 protein, known to exert anti-apoptotic activity. Lysis of tumours by CD8-enriched cultures and CD8 þ clones was Ca 2þ-dependent and could not be modified by an anti-Fas MoAb. In CD4-enriched cultures or CD4 þ clones with cytotoxic potential against tumour cells, cytotoxicity was also Ca 2þ-dependent. As Ca 2þdependent cytotoxicity is usually the result of secretion of perforin/granzyme-B, we investigated the presence of perforin in cytotoxic CD4 þ clones and demonstrated the presence of granular deposits of this enzyme in some of the CD4 þ clones. Although an anti-Fas MoAb did not block the lysis of melanoma targets by CD4 þ clones, the examination of Fas-dependent targets demonstrated that these clones also had the potential to kill by the Fas/Fas ligand system. These data suggest that the predominant mechanism in tumour killing by TIL appears to be perforin-granzyme-dependent, and that the solid tumour cell lines we studied are less susceptible to Fas-mediated apoptosis. As non-apoptotic pathways may enhance tumour immunogenicity, exploitation of the perforin-granzyme-dependent cytotoxic T lymphocyte (CTL) pathways may be important for achieving successful anti-tumour responses.
Immunochemotherapy of a Murine Thymoma with the Use of Idarubicin Monoclonal Antibody Conjugates
Cancer Research, 1988
Idarubicin is a derivative of daunomycin and is characterized by the absence of the methoxyl group at the C-4 position. It has been reported to have greater therapeutic effect than daunomycin. Idarubicin was chemically coupled to a monoclonal antibody to the murine Ly-2.1 alloantigen and the cytotoxicity of the drug-monoclonal antibody conju gate «TV«* free idarubicin was tested in vitro against I v-2f and Ly-2t umor cell lines. Some loss of idarubicin activity occurred upon conjuga tion to the monoclonal antibody; however, antibody activity was preserved and selective cytotoxicity for the I .y-2*cell line was observed. By contrast free idarubicin was equally cytotoxic for all cell lines (Ly-2* and Ly-2~). Idarubicin-anti-Ly-2.1 conjugates were tested for their capacity to inhibit solid tumor growth in (Ly-2.r, Ly-2.2+) (C57BL/6 x BALB/c)F, mice while their nonspecific effects were monitored by histológica!examina tion. The idarubicin-anti-Ly-2.1 conjugates when injected i.v. or directly into the tumor were observed to inhibit tumor growth more effectively than idarubicin or anti-Ly-2.1 alone, with smaller tumors being com pletely eradicated within several days of the completion of treatment.
Recent Developments in Cancer Treatment: A Review
Pharmaceutical Regulatory Affairs: Open Access, 2014
According to the latest cancer statistics presented worldwide, there has been a dramatic increase in the rates of occurrence of some cancers, particularly in the more developed countries. Although many therapeutic strategies to prevent and/or cure this disease have been proposed and evaluated by clinicians and researchers, there remains a need to find more effective approaches. Side effects such as toxicity and drug resistance are two of the most frequent problems faced during chemotherapy. Small-molecule drugs are being intensively pursued as new anticancer therapeutics. Oncology drug discovery has benefited significantly from progress in understanding how to target kinases with small molecules that were found to be correlated with the disease. One reason for this is that many kinases have been found to be intimately involved in the processes leading to tumor cell proliferation and survival. Monoclonal antibodies, that are produced in vitro, can be used in cancer treatment in a number of ways. They may enhance the immune system by reacting with certain types of cancer cells. They can be programmed to act against specific cell growth factors to interfere with the growth of cancer cells. Furthermore, they may be linked to anticancer drugs, radioactive substances, other biologic therapies, or other toxins (antibody-drug conjugates). Finally, the usage of cytotoxic monoclonal antibodies during the process of bone marrow transplantation may be a key to improve the efficacy of the method.
Cancer Immunology, Immunotherapy, 2006
Linkage of doxorubicin (Dox) to a water-soluble synthetic N-(2-hydroxypropyl)methacrylamide copolymer (PHPMA) eliminates most of the systemic toxicity of the free drug. In EL-4 lymphoma-bearing C57BL/6 mice, a complete regression of pre-established tumours has been achieved upon treatment with Dox-PHPMA-HuIg conjugate. The treatment was effective using a range of regimens and dosages, ranging from 62.5 to 100% cured mice treated with a single dose of 10-20 mg of Dox eq./kg, respectively. Fractionated dosages producing lower levels of the conjugate for a prolonged time period had substantial curative capacity as well. The cured mice developed anti-tumour protection as they rejected subsequently re-transplanted original tumour. The proportion of tumour-protected mice inversely reflected the effectiveness of the primary treatment. The treatment protocol leading to 50% of cured mice produced only protected mice, while no mice treated with early treatment regimen (i.e. starting on day 1 after tumour transplantation) rejected the re-transplanted tumour. Exposure of the host to the cancer cells was a prerequisite for developing protection. The antitumour memory was long lasting and specific against the original tumour, as the cured mice did not reject another syngeneic tumour, melanoma B16-F10. The immunity was transferable to naı¨ve recipients in in vivo neutralization assay by spleen cells or CD8 + lymphocytes derived from cured animals. We propose an effective treatment strategy which eradicates tumours without harming the protective immune anti-cancer responses.