Publisher Summary The existence of any substantial interaction between different agents that are used clinically or to which man is exposed environmentally is potentially of great importance. One agent may affect another's absorption, metabolism, or excretion. It may alter tissue sensitivity to another agent, and may react with it physically or chemically. A variety of different criteria have been devised for deciding whether the agents in a combination interact pharmacologically. The purpose of this chapter is to examine these criteria critically for the progress in this field. To summarize, the effect–summation criterion may be used when the effects of all the agents in a combination are directly proportional to dose. The key to any criterion for examining interactions between different agents lies in the definition of zero interaction. The interactions that can be analyzed by constructing isoboles or calculating interaction indices are not restricted to cases in which all agents in a combination produce the effect under consideration. The therapeutic significance of interactions between agents requires careful consideration.

Criteria for Analyzing Interactions between Biologically Active Agents

Cancer of the breast: the past decade (first of two parts).

The results of treatment of 198 patients with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) for Hodgkin's disease were analyzed after a median of 14 years of follow-up. Throughout the period of follow-up, 103 patients have remained continuously free of disease. Review of biopsy specimens of 43 patients originally classified as Hodgkin's disease, lymphocyte-depleted type, revealed that ten of these patients actually had diffuse immunoblastic or large cell non-Hodgkin's lymphomas. Of the 188 patients with Hodgkin's disease, 157 achieved a complete response (CR) (84%), and 66% of them (101 patients) have remained disease-free more than 10 years from the end of treatment. Absence of B symptoms and receiving higher doses of vincristine were factors associated with a higher CR rate and longer survival. Patients entering complete remission in five cycles or less had significantly longer remissions than those requiring six or more cycles. Forty-eight percent of the Hodgkin's disease patients h...

Twenty years of MOPP therapy for Hodgkin's disease.

MCF-7 human mammary carcinoma cells were inoculated into 150-sq cm flasks at 3 X 10(5) cells/flask, and after a lag period of about 48 hr, these cells grew exponentially for 5 days with a mean population doubling time of about 24 hr. During exponential growth, 80 to 90% of cells were in the "rapidly cycling" pool, the clonogenic fraction was 50 to 60%, and the mean percentage of cells in the G0-G1, S, and G2 + M phases of the cell cycle was 48.9 +/- 0.6% (S.E.), 39.4 +/- 0.6%, and 11.6 +/- 0.3%, respectively. These parameters changed rapidly between Days 7 and 13 when plateau phase was reached. Between Days 13 and 18, 74.8 +/- 0.7% of cells were in G0-G1, 15.3 +/- 0.4% were in S, and 9.8 +/- 0.6% were in G2 + M phase. Only about 30% of these cells were cycling rapidly, and the clonogenic fraction had fallen to less than 10%. Tamoxifen induced a dose-dependent decrease in the growth rate of exponentially growing cells, which was accompanied by a dose-dependent increase in percentage of G0-G1-phase cells, and a decline in percentage of S-phase cells. At doses greater than or equal to 10 microM, a 24-hr pulse of tamoxifen was cytotoxic to exponentially growing cells. Plateau-phase cells were less sensitive to these effects of tamoxifen. In an attempt to define the kinetic basis of the G0-G1 accumulation induced by tamoxifen, asynchronous MCF-7 cells were pretreated for 42 hr with various doses of tamoxifen, and the rate of efflux of cells from the G0-G1 phase of the cell cycle was assessed by blocking their reentry into G1 with ICRF 159. Following treatment of control cultures with ICRF 159, two populations of cells were distinguished by their rates of efflux from G0-G1 phase. The majority of cells left G0-G1 rapidly with a mean t1/2 of 2.3 hr ("rapidly cycling" cells). However, about 18% of cells had a much slower rate of exit with a mean t1/2 of about 30 hr ("slowly cycling" cells). Pretreatment with tamoxifen resulted in a dose-dependent decrease in the proportion of rapidly cycling cells and an increase in the proportion of cells with slow G1 transit times. Although this appeared to be the predominant effect, tamoxifen also decreased the rate at which the slowly cycling cells traversed G1. Simultaneous treatment with estradiol returned these parameters to control values at doses of tamoxifen less than or equal to 5 microM, partially reversed the effect of 7.5 microM tamoxifen, but was without effect on the arrest of cell cycle progression induced by 10 microM tamoxifen. It is concluded that cells accumulate in G0-G1 following tamoxifen treatment due to an increase in the proportion of slowly cycling cells at the expense of a population of rapidly cycling cells, which appear to be relatively uninfluenced by the drug.

https://cancerres.aacrjournals.org/content/canres/43/9/3998.full.pdf

Cell Proliferation Kinetics of MCF-7 Human Mammary Carcinoma Cells in Culture and Effects of Tamoxifen on Exponentially Growing and Plateau-Phase Cells

We consider the hypothesis that estrogen control of hormone dependent breast cancer is mediated by autocrine and paracrine growth factors secreted by the breast cancer cells themselves. Though we show direct, unmediated effects of estrogen on specific cell functions, we also provide evidence that human breast cancer cells secrete a collection of growth factors (IGF-I, TGFα, TGFβ, a PDGF-like competency factor, and at least one new epithelial colony stimulating factor). Some of these are estrogen-regulated in hormone dependent cells, and are constitutively increased in cells which acquire independence either spontaneously or byras transfection. Collectively, the secreted growth factors are capable of promoting tumor formation by MCF-7 cells in nude mice, though not to the same extent as estrogens. There would seem to be potential for clinical intervention in the autocrine and paracrine control of breast cancer cells, including some cells which are no longer dependent on estrogens.

Autocrine and paracrine growth regulation of human breast cancer

The effect of 17β-estradiol on an estrogen receptor-positive human breast cancer cell line (MCF-7) was studied. Low concentrations (10 -9 m) of 17β-estradiol enhanced the rate of cell proliferation; the overall cell cycle time was shortened; and the proportion of cells in the S phase increased. Higher concentrations (10 -7 m) suppressed proliferation and slightly decreased the proportion of cells in DNA synthesis. When combined with 1-β-d-arabinofuranosylcytosine, an S-phase-specific chemotherapeutic agent, 10 -9 m 17β-estradiol enhanced cell killing. This enhancement was not observed with 10 -7 m 17β-estradiol. Kinetic changes caused by hormones have profound implications in clinical therapy, since the efficacy of cycle active agents may be altered.

Proliferation Kinetics of a Human Breast Cancer Line in Vitro following Treatment with 17β-Estradiol and 1-β-d-Arabinofuranosylcytosine

In many centers, laparotomy and splenectomy is an important procedure in the staging and management of Hodgkin's disease patients. Surgery usually is performed under general anesthesia with endotracheal intubation. Acute complications of such anesthesia in patients with mediastinal disease prompted a review of the anesthesia experience for any procedure in all Hodgkin's disease patients seen at our center from April 1969 through December 1973. Acute life-threatening complications occurred in 5 of 74 intubation anesthesias carried out in untreated patients with mediastinal and/or hilar disease; no complications were seen in 24 anesthesias performed after radiation therapy of mediastinal disease, or in 78 anesthesias in patients without intrathoracic disease. The incidence of anesthesia complications was related to mediastinal mass size. Hodgkin's disease patients with significant mediastinal masses should be treated before surgery whenever possible.

Mediastinal Hodgkin's disease: A possible danger for intubation anesthesia: Intubation danger in Hodgkin's disease

Between 1971 and 1975, 55 patients underwent palliative radiation therapy for symptomatic hepatic metastasis. Most patients received 2400 rad in 300 rad fractions to the entire liver. There were 31 patients who received concomitant chemotherapy, and 14 who were prior chemotherapy failures. Ninety percent of the patients with symptomatic pain and liver enlargement and significant palliation of their symptoms. The median survival of the entire group was 4.5 months, while those patients experiencing an excellent response (21) had a median survival of 9 months. The median survival of patients having an excellent response to radiation is comparable to that of patients having regional arterial chemotherapy while incuring fewer complications. The overall complication rate of those patients completing therapy (50) was 12%.

Palliation of hepatic metastasis.

Interaction between radiation and Adriamycin damage reduced the width of the shoulder of the X-ray survival curve. This effect was found to persist for at least 24 hr after Adriamycin treatment. Adriamycin did not affect radiation damage when cells were treated either before two-dose fractionation or with the drug present between X-ray exposures. Adriamycin is unique in that its major effect on radiation response is to reduce the survival curve shoulder without affecting two-dose recovery. It is suggested that Adriamycin and radiation produce independent classes of damage that are expressed mutually for killing, with regard to the registration of sublethal radiation damage, but that repair of the latter is unaffected by Adriamycin.

https://cancerres.aacrjournals.org/content/canres/37/6/1624.full.pdf

The Interaction between Radiation and Adriamycin Damage in Mammalian Cells

To assess the importance of radiation dose fraction size in the treatment of malignant melanomas, the records of 48 patients (83 sites) treated at Tufts-New England Medical Center from 1971 to 1979 have been retrospectively reviewed. During this period, the dose fractionation schemes evolved from standard fraction size to large-dose techniques. Radiation fraction size was observed to be the major factor in the clinical response of melanoma. Fractions of 600-800 rad resulted in the best overall response (80%). The rapid fractionation scheme of 800-400-400 rad on successive days resulted in intermediate response (58%) and may be useful for the palliative treatment of selected patients.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%2819810315%2947%3A6%3C1262%3A%3AAID-CNCR2820470606%3E3.0.CO%3B2-H

Anthony J. Piro

Papers

Proliferation Kinetics of a Human Breast Cancer Line in Vitro following Treatment with 17β-Estradiol and 1-β-d-Arabinofuranosylcytosine

Mediastinal Hodgkin's disease: A possible danger for intubation anesthesia: Intubation danger in Hodgkin's disease

Palliation of hepatic metastasis.

The Interaction between Radiation and Adriamycin Damage in Mammalian Cells

Radiation therapy of malignant melanomas: an evaluation of clinically used fractionation schemes