Synthesis and antimetastatic properties of steroeoisomeric trycylic bis(dioxopiperazine) analogues in a B16 melanoma model.

The synthesis for trans and cis tricyclic bis(dioxopiperazine)s 5 and 6 from pyrazine-2,3-dicarboxamide (7) is described. Stereoselective antimetastatic activity differences for these analogues were observed following pretreatment of B16-F10 melanoma cells in vitro. Activities for these isomers were compared with selected intermediates, and the data are discussed in relation to previous results obtained with cis- and trans-cyclopropane analogues.

Analysis of disability resulting from treatment including radical neck dissection or modified neck dissection.

A multiinstitutional study to define the impact of total treatment programs involving radical neck dissection (RND) and modified neck dissection (MND) on patients' permanent disability was undertaken. A total of 243 patient responses were included in the study. Comparative analyses between the treatment groups show no advantage of one surgical operation over the other in returning patients to their pretreatment employment status. Radiation therapy was identified as adding significantly to the patient's permanent disability.

Economic differentials in cancer survival: a multivariate analysis.

This study investigates economic differentials in cancer survival using more adequate measures of economic status and controlling for confounding variables more systematically than earlier studies. For 1180 white males, a variant of the Cox regression model is employed to estimate the direct and interaction effects of economic status on survivorship, controlling for age at diagnosis, stage, severity of disease, and initial course of treatment. The results do not show a strong relationship. Estimates of direct or main economic effects rarely reach even borderline statistical significance; they are highly sensitive to model specification and the measurement of the economic variable. An equally weak interaction effect between economic status and stage is detected in several cases, but the parameter estimates are unstable. Such measurement and specification errors have probably exaggerated the importance of economic factors in cancer survival in earlier investigations.

Alveolar macrophage subpopulations identified by differential centrifugation on a discontinuous albumin density gradient.

Mononuclear phagocytes are functionally heterogeneous. To study the relationship of the heterogeneous populations of macrophages from the lung, alveolar macrophages from Syrian hamsters that had been immunized and rechallenged intratracheally with Mycobacterium bovis (Strain BCG) were separated by discontinuous albumin gradient centrifugation into 5 subpopulations designated A, B, C, D, and E. An activated alveolar macrophage subpopulation (defined by the ability to destroy tumor target cells) was enriched only in fraction D. Cells in fraction D destroyed 40% of the tumor cells, whereas unseparated alveolar macrophages destroyed 29%. Fractions A, B, C, and E destroyed less than 15% of the tumor cells. The subpopulations were functionally heterogeneous with regard to chemotactic responsiveness, Fc receptor activity, and phagocytic activity. Incubation of the subpopulations with a lymphocyte supernatant from spleen cells stimulated with concanavalin A enhanced the cytotoxic activity of fraction D and activated cells in fractions C and E to destroy tumor cells. Neither resident alveolar macrophages nor any of the subpopulations destroyed tumor cells. Only resident fraction D cells killed tumor cells when incubated with lymphokine containing supernatant fluids. The results are consistent with the hypothesis that some subpopulations of alveolar macrophages may be related and exist as a continuum of differentiation.

Endocrine ablation in breast cancer patients who have failed cytotoxic therapy.

Between 1972 and 1979, forty-six women underwent endocrine ablative surgery, having failed combinations of chemotherapy, radiation, and surgery (including oophorectomy). All had clinically measurable disease; nearly half were afflicted with bone pain. Each was judged to be a candidate for the procedure by estrogen receptor studies (52%), response to L-dopa (39%), or response to prior oophorectomy (8%). All were followed to their death or to the present, with a minimum of 12 months for those alive. Thirty-one (67%) were improved, and disease was arrested in five (11%) for a median time of 13.5 months. There was no difference in response rates or intervals between estrogen receptor-positive and L-dopa-positive groups. Response was not correlated with disease-free interval or menopausal status. Best results were achieved in those with metastases confined to an organ system, particularly the skeletal complex. The procedure is withheld in those with brain metastases. Postablative chemotherapy appeared to prolong the control interval, though numbers are small. The low morbidity and mortality (one death) of midline adrenaloophorectomy combined with the high incidence of recapture of disease leads us to recommend this procedure in appropriately selected patients who have previously failed other therapeutic modalities.

Effect of stereoisomers related to ICRF-159 on metastasis of B16 melanoma.

The antitumour effects of ICRF-159 and related analogues were evaluated using the B16 melanoma. Treatment of mice with ICRF-159 inhibited tumour growth, while each of the analogues, trans-4,4(1)-(1,2-cyclopropandiyl) bis (2,6-piperazinedione) (trans-5), and cis-4,4(1)-(1,2-cyclopropandiyl) bis (2,6-piperazinedione) (cis-7) independently accelerated primary tumour growth. Pretreatment of B16 melanoma cultures either with ICRF-159 or the analogue cis-7 decreased the yield of lung-colonies following i.v. injection of tumour cells. In contrast, pretreatment of tumour cells with the trans-5 analogue led to an increase in lung colonies. The effect on colony formation in vitro of these analogues correlated with increased growth in vivo, and not with lung colony formation.