Biological therapy of cancer

Interferons and monoclonal antibodies are among the most promising biological approaches to cancer treatment which have so far been investigated. Both natural and recombinant interferon-alpha preparations have shown activity in a number of trials in hematologic malignancies, even in previously treated patients; activity in solid tumors, however, has been limited. Unconjugated monoclonal antibodies have been safely administered in several small trials and have had therapeutic value on occasion. In spite of a number of remaining problems and questions, monoclonal antibodies and their conjugates seem likely to find a number of distinct roles in cancer treatment; elimination of micrometastases and purging of bone marrow for grafting may be among these roles.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44207/1/10549_2005_Article_BF01886730.pd

Sequence and drug susceptibility of subtype C reverse transcriptase from human immunodeficiency virus type 1 seroconverters in Zimbabwe.

Naturally occurring human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) variability has implications for the success of antiretroviral therapy. We determined the sequence of the polymerase-coding region of RT from virus isolates from 12 Zimbabwean individuals recently infected with HIV-1. The 12 RT sequences differed from the consensus B RT sequence at 10.5% of nucleotides and 5.8% of amino acids. Susceptibility testing of five isolates to zidovudine, didanosine, lamivudine, and nevirapine demonstrated susceptibilities similar to those of wild-type subtype B isolates. Phylogenetic analysis of 40 HIV-1 RT sequences, including the 12 Zimbabwean subtype C sequences, 11 subtype B sequences, and the 17 remaining published non-subtype B sequences showed sufficient intrasubtype RT sequence variation to differentiate subtype A, B, C, and D isolates. Five recently reported subtype C RT sequences from India grouped with the Zimbabwean subtype C sequences but had significantly less intraisolate sequence variation. Both intra- and intersubtype RT comparisons were notable for extraordinarily high ratios of synonymous to nonsynonymous differences. Although substitutions in the HIV-1 RT gene are limited by functional constraints, variation between RT sequences demonstrates phylogenetic relationships that parallel env and gag gene variation

Follow-up observations on the effect of human leukocyte interferon in non-Hodgkin's lymphoma

Follow-up data for 11 patients with non-Hodgkin's lymphoma treated with partially purified human leukocyte interferon is presented. The interferon preparation used was 0.1% pure and treatment consisted of 5 x 10(6) U given intramuscularly twice daily for 60 injections. One complete, three partial, and three minimal responses were observed in five of seven evaluable patients with nodular non-Hodgkin's lymphoma. Duration of response appears to be from 6 to 12 mo. One patient achieved a second partial response on retreatment with interferon in spite of having received chemotherapy in the interval between interferon treatments. No responses were seen in three patients with rapidly progressive diffuse histiocytic lymphoma. Dose-limiting toxicity is leukopenia, which necessitated modification or cessation of treatment in three patients. Nonhematologic toxicities consisted of fever, malaise, arthralgia, and loss of appetite. In conclusion, interferon has activity against non-Hodgkin's lymphoma, and prior treatment with chemotherapy does not preclude a response to interferon.</jats:p

Follow-up observations on the effect of human leukocyte interferon in non-Hodgkin's lymphoma

Abstract Follow-up data for 11 patients with non-Hodgkin's lymphoma treated with partially purified human leukocyte interferon is presented. The interferon preparation used was 0.1% pure and treatment consisted of 5 x 10(6) U given intramuscularly twice daily for 60 injections. One complete, three partial, and three minimal responses were observed in five of seven evaluable patients with nodular non-Hodgkin's lymphoma. Duration of response appears to be from 6 to 12 mo. One patient achieved a second partial response on retreatment with interferon in spite of having received chemotherapy in the interval between interferon treatments. No responses were seen in three patients with rapidly progressive diffuse histiocytic lymphoma. Dose-limiting toxicity is leukopenia, which necessitated modification or cessation of treatment in three patients. Nonhematologic toxicities consisted of fever, malaise, arthralgia, and loss of appetite. In conclusion, interferon has activity against non-Hodgkin's lymphoma, and prior treatment with chemotherapy does not preclude a response to interferon.</jats:p

Drug resistance and heterogeneous long-term virologic responses of human immunodeficiency virus type 1-infected subjects to zidovudine and didanosine combination therapy

Plasma human immunodeficiency virus (HIV) type 1 RNA levels, CD4 lymphocyte changes, and drug resistance were studied in HIV-infected patients with 200-500 CD4 lymphocytes/μL who received zidovudine and didanosine combination therapy for 2 years. Among 35 patients, 10 had sustained and 16 had transient >10-fold reductions in HIV RNA; 9 did not have 10-fold HIV RNA reductions. Only patients with sustained HIV suppression maintained increased CD4 cell counts for 2 years (370 to 501 cells/μL; P = .006). Patients with transient HIV suppression were more likely to develop drug-resistant HIV strains (12/16 vs. 5/19, P = .01) and reverse transcriptase (RT) mutations (4.5 vs. 2.5/strain; P = .02) than were patients with sustained or no HIV suppression. Zidovudine resistance occurred with RT mutations at codons 41, 67, 70, 215, and 219. Multidrug resistance occurred with mutations at codons 62, 75, 77, 116, and 151. Mutations occurred at codons 60, 68, 118, 210, and 228 in ≥4 patients each. Heterogeneity exists among individual virologic responses to zidovudine and didanosine combination therapy. HIV resistance mechanisms during combination therapy appear more complex than reported with monotherapy

Multidrug-resistant human immunodeficiency virus type 1 strains resulting from combination antiretroviral therapy.

Multidrug-resistant human immunodeficiency virus type 1 (HIV-1) strains with reverse transcriptase (RT) mutations at codons A62--&gt;V, V75--&gt;I, F77--&gt;L, F116--&gt;Y, and Q151--&gt;M have been reported in patients receiving combination therapy with zidovudine (AZT) and didanosine (ddI). Infectious clones with each mutation alone, all five mutations together, and various combinations of mutations were created by site-directed mutagenesis. Mutation Q151--&gt;M conferred partial resistance to AZT, ddI, zalcitibine, and stavudine, whereas a combination of four mutations conferred increased resistance to AZT, ddI, zalcitibine, and stavudine. The positions of residues 75, 77, and 151 in the three-dimensional crystal structure of HIV-1 RT suggest that these residues may affect the ability of the enzyme to discriminate between deoxynucleoside triphosphates and nucleoside analog RT inhibitors. Replication experiments showed that clones with mutation F77--&gt;L but without V75--&gt;I (HIV-1(77), HIV-1(77,151), and HIV-1(77,116,151) had attenuated growth compared with that of the original HIV-1NL4-3 strain and strains containing mutations at both positions 75 and 77 (HIV-1(75,77,151) and HIV-1(75,77,116,15)). Sequence analysis of viral RNA and proviral DNA from several patients indicated that RT mutations developed in a sequential and cumulative pattern over the course of a 2- to 4-year observation period. The present results suggest that drug resistance and viral replicative capacity both may play a role in selection of HIV-1 RT mutations