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PubMed1982

Carcinoid tumors of the uterine cervix: response to combination chemotherapy and radiotherapy.

Two cases of advanced (Stage III) carcinoid. tumors of the cervix are presented. Initial treatment in both cases consisted of combination chemotherapy (CCNU, cyclophosphamide and methotrexate) administered in the same regimen used in the treatment of small cell carcinoma of the lung. Initial response in the first case was remarkable, but toxic side effects delayed further treatment. Local tumor progression followed resulting in bilateral complete ureteric obstruction. Radiation therapy was discontinued before an effective dose could be delivered, and the patient expired in uremic coma. In the second case, initial response to chemotherapy was not as effective, but radiation therapy seemed to produce local control of the disease. Review of the English literature produced 21 additional cases of carcinoid tumors of the cervix: eight Stage I, seven Stage II, four Stage III, and one Stage IV. No firm conclusions with regard to therapy could be drawn from such small numbers.

Adult↗
PubMed1982

[Chemotherapy of stomach cancer].

In recent years several studies have been performed to improve the chemotherapy of metastatic gastric carcinoma. It is now established that combined chemotherapy for example with 5-Fluorouracil, adriamycin and mitomycin C or nitrosourea derivatives is superior to monotherapy with 5-Fluorouracil. With this combined chemotherapy, response rates of 30-40% can be achieved with prolonged medium survival time in responders. In locally advanced tumors the combined use of radiation and chemotherapy probably will be able to improve the results. Future studies are needed to show the role of adjuvant chemotherapy in gastric cancer patients after surgery.

Adenocarcinoma↗
PubMed1983

In vivo potentiation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea by the radiation sensitizer benznidazole.

Recent studies in mouse tumor systems have indicated a potential therapeutic advantage in combining the radiosensitizer misonidazole (MISO) with cancer chemotherapy drugs. One agent the antitumor activity of which has been enhanced to a greater extent than its hematological or gastrointestinal toxicities is the nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). Recently, sensitizers more lipophylic than MISO have been reported to give greater tumor response enhancement when combined with CCNU. The present studies compared the potential therapeutic benefit of combining MISO (partition coefficient, 0.43) or benznidazole (BENZO) (partition coefficient, 8.5) in KHT sarcoma or RIF-1 tumor-bearing C3H mice. Both sensitizers were administered i.p. and given either 30 min before (BENZO) or simultaneously with (MISO) the chemotherapeutic agent. Survival of clonogenic tumor cells assessed 22 to 24 hr after treatment or in situ tumor growth delay were used as assays of tumor response. Normal tissue toxicity was determined using the drug dose yielding 50% animal lethality in 30 days end point. When combined with CCNU, doses of MISO (5.0 mmol/kg) or BENZO (0.3 mmol/kg) were found to yield approximately equivalent increases in both the tumor effect (enhancement ratio, approximately 1.8 to 2.0) and normal tissue toxicity (enhancement ratio approximately 1.3 to 1.4). Both sensitizers therefore led to a therapeutic benefit. However, although a approximately 10-fold lower dose of the more lipophylic sensitizer BENZO proved to be as effective as MISO at enhancing the tumoricidal effects of CCNU, this dose reduction did not result in a greater therapeutic gain for BENZO.

Animals↗
PubMed1983

Use of phenobarbital and high doses of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea in the treatment of brain tumor-bearing mice.

It has been shown that the nitrosoureas are substrates for hepatic microsomal enzymes in vitro and that phenobarbital (PB) administered in multiple doses prior to nitrosourea administration significantly reduces the activity of the nitrosoureas in murine brain tumor models. In the present study, the effect of PB on 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) was assessed by determining the CCNU dose which would result in the long-term survival of 50% of the treated mice, and the CCNU dose which would result in the toxic death of 50% of the treated mice, with or without PB pretreatment in C56BL/6J mice. The therapeutic index, the CCNU dose which would result in the long-term survival of 50% of the treated mice, per the CCNU dose which would result in the toxic death of 50% of the treated mice, without PB pretreatment was 2.1; the therapeutic index of CCNU after PB pretreatment was 1.7. There is no significant difference between the therapeutic indices. Thus, the reduction in the tumoricidal activity of CCNU after PB pretreatment was restored by increasing the dose of CCNU without a significant change in its lethal toxicity.l

Animals↗
PubMed1983

CCNU toxicity after an overdose in a patient with Hodgkin's disease. Effects on colony-forming cells (CFU-C) and colony-stimulating activity (CSA).

An overdose of CCNU (600 mg over a 15-d period) was unintentionally ingested by a patient with advanced Hodgkin's disease subjected to combination chemotherapy. A severe bone marrow depression occurred 3 weeks after the start of the CCNU treatment. The nadir of the platelet count was reached after 4 weeks and that of the granulocyte count after 5 weeks. At the nadir of the white blood cell count, colony-forming cells (CFU-C) were found in significantly reduced numbers in the bone marrow, and were not found at all in the peripheral blood; the amount of colony-stimulating activity (CSA) produced by peripheral blood cells was reduced. However, the cells producing CSA recovered earlier than the CFU-C, and the CSA peak value was reached about 1 week before the peak value for CFU-C in the bone marrow. Thus, in vivo CSA-producing cells appeared to be more resistant to CCNU than were CFU-C, and their recovery appeared to be a prerequisite for the recovery of CFU-C and myelopoietic cells.

Animals↗
PubMedDate not supplied

Immunochemotherapy in 34 cases of oat cell carcinoma of the lung with 19 complete responses.

Thirty-four previously untreated patients with oat cell carcinoma of the lung were treated with a myelotoxic combination of cyclophosphamide, adriamycin, methotrexate, CCNU, and Corynebacterium parvum (regimen A) every 4 weeks, interspersed with a non-myelotoxic combination including bleomycin, vincristine, dehydroemetine, and Corynebacterium parvum (regimen B) weekly the other 3 weeks or when hematologic toxicity prohibited administration of regimen A. Hematologic toxicity was frequent but was never a serious problem except in two cases of profound leukopenia in which fatal supervening infection occurred. Nineteen patients in this series (56%) showed a complete response lasting from 4+ to 65+ months. Eight of these patients are still alive with a followup of 6+ to 65+ months. Nine patients (26%) showed a partial response (greater than 50%) lasting 1-10+ months. Only one patient in this group is surviving (10+ months). The overall response rate was thus 82%. It is concluded from this study that only a complete response has any significant effect on survival, the benefit of a partial response over no response being only slight. The results achieved are compared to those of available series in the literature and from this comparison strategic deductions for the treatment of oat cell carcinoma of the lung are made.

Adult↗
PubMed1983

In vivo chemosensitization by misonidazole in sensitive and resistant tumor lines.

In an attempt to evaluate whether the radiation sensitizer misonidazole (MISO) could enhance the responsiveness of chemoresistant tumors, MISO was combined with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and/or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) for the treatment of BALB/c X DBA/2 F1 (hereafter called CD2F1) and C3H/HeJ mice bearing nitrosourea-resistant L1210/BCNU or KHT/CCR tumors, respectively. To determine whether comparable degrees of enhancement could be achieved in sensitive and resistant tumor lines, the magnitude of chemosensitization produced by treating the resistant tumors with the MISO-nitrosourea combinations was compared to the chemopotentiation produced in similarly treated nitrosourea-sensitive tumor lines from which the resistant lines had been derived. As evidenced by increased cure probabilities, the addition of MISO [5.0 mmol/kg (1.0 mg/g)] significantly potentiated the response of the parental nitrosourea-sensitive L1210/0 tumor to a 20-mg/kg dose of CCNU. When combined with doses of CCNU lower than 20 mg/kg or with BCNU, MISO failed to significantly modify the response of the L1210/0 tumor. Significant chemosensitization also was evident when 2.5- and 1.25-mmol/kg doses of MISO were used in combination with CCNU at 20 mg/kg. The effectiveness of BCNU and CCNU against the nitrosourea-resistant L1210/BCNU tumor was not significantly improved by MISO (5.0 mmol/kg), even when the sensitizer was combined with doses of nitrosoureas approaching 10% lethal dose (60 days) concentrations. In contrast, the effectiveness of CCNU against the parental KHT and resistant KHT/CCR tumors, assessed using a tumor regrowth assay, was equally enhanced by simultaneous MISO treatment. Therefore, one cannot safely predict the extent of enhancement which might result from the addition of MISO to a chemotherapeutic regimen based solely on the responsiveness of the tumor to the chemotherapy drug(s) alone.

Animals↗
PubMed1977

Pharmacokinetic studies of a transplantable murine renal adenocarcinoma.

An animal model to investigate new therapeutic approaches for the treatment of renal adenocarcinoma has been further studied. This model is based on a transplantable murine renal adenocarcinoma whose growth follows Gompertzian kinetics, relates to tumor RNA and DNA content, and also correlates with the rate of tumor DNA synthesis. This model in the current study was also evaluated for the ability of various therapeutic agents to inhibit tumor DNA synthesis. Such tests may be valuable for the preclinical screening of potentially useful drugs and may provide insight into fundamental aspects of tumor control. In this study, CCNU, BCNU, and adriamycin were potent inhibitors of tumor DNA synthesis whereas cytosine arabinoside, bleomycin, and cyclophosphamide were not. These observations were confirmed by autoradiography and correlated with other experimental end points of tumor therapy such as tumor weight and animal survival. This preclinical screening model is an effective and helpful means whereby new drugs and drug combinations can be tested for potential use in human renal cell carcinoma.

Adenocarcinoma↗
PubMed1982

[Combination chemotherapy of Hodgkin's disease with vincristine, cyclophosphamide, procarbazine, and prednisolone].

Nineteen patients with stages II B-IV of Hodgkin's disease were treated with a combination of vincristine, cyclophosphamide, procarbazine, and prednisolone (CVPP regimen), given in a 3 week intervals for 3 months. Eighteen patients were available for responses. A complete remission (CR) was obtained in 9 (50%) out of 18 patients. The median duration of CR and relapse-free survival were 7 months and 26+ months, respectively. Hematologic toxicity was mild, although occasionally cumulative for aged patients and for previously treated patients. Other toxicities such as alopecia and neurotoxicity were troublesome but reversible. Thus, a further study by modification of the regimen warranted to improve the response rate and relapse-free survival.

Adult↗
PubMed1980

Comparison of growth delay and cell survival as end-points of tumour response following treatment with combinations of cytotoxic agents.

The response of the B16 melanoma to the simultaneous combination of CY plus CCNU was examined using cell survival and growth delay endpoints. Combination data were evaluated either by applying the simple concept that an additive combination response is equal to the sum of the single agent responses or by constructing additivity envelopes as described recently by Steel & Peckham (1979), in order to take account of non-linear dose-response curves. Although cell survival was additive on the simple basis, tumour growth delay was greater than predicted by the simple concept, but still within the additivity envelopes. This apparent anomaly may, however, be explained by considering the relationship between the two endpoints. Although the extent of growth delay of a tumour is dependent on the level of tumor cell survival, it is also influenced by other factors such as the rate of regrowth of surviving tumour cells, which may in turn be affected by systemic host effects resulting from the same treatment. We have recently shown that tumour cell repopulation after CY treatment is much slower than after CCNU, and in this paper we demonstrate by means of a transplantation experiment that this is probably due to a systemic host effect of CY. Thus, the observed growth delay response of the combination is consistent with a model in which the agents produce additive cell killing, but the subsequent tumour cell repopulation is retarded by a systemic effect of CY.

Animals↗