Galen L. Wampler

Intracerebral metastases in solid‐tumor patients: Natural history and results of treatment

In order to determine the natural history and results of treatment of intracerebral metastases in solid‐tumor patients, the records of 191 patients with an antemortem diagnosis of intracerebral metastasis made during the period from August 1974 to November 1978 were reviewed. Malignancies included lung (122 patients), breast (26), unknown primary (16), melanoma (8), colorectal (6), hypernephroma (4), and others (12). Favorable prognostic factors included solitary brain metastasis (P < 0.001), ambulatory performance status (P < 0.001), symptoms of headache (P < 0.001), or visual disturbances (P < 0.02), and estrogen receptor positivity in breast cancer patients (P = 0.055). Poor prognostic factors included advanced age (P < 0.04) and evidence of impaired consciousness, i.e., disorientation, lethargy, stupor, or coma (P < 0.007). Median survival time after diagnosis of intracerebral metastasis was 3.7 months for the entire series. In those patients with a single intracerebral metastasis and minimal tumor burden, the type of treatment used had a significant impact on survival. Those cases treated with surgery and radiation had a median survival time of 9.7 months versus 3.7 months for those treated with radiation alone (P < 0.02). When using a proportional hazard regression analysis to adjust for the three most important prognostic factors, treatment (surgery and radiation versus radiation alone) still appeared to be important. Intracerebral metastases were the immediate or contributing cause of death in 50% of the patients in this series. Patients at greater risk of dying of intracerebral metastases included those in whom the brain was the first site of distant metastasis, those with an intracerebral metastasis from an unknown primary site, and those whose presentation of malignancy was with symptoms of a brain metastasis. Although the therapeutic goal in intracerebral metastases is generally palliative, it appears that there are categories of cases that may benefit from more aggressive treatment.

Antitumor activity and toxicity of peroxo heteroligand vanadates(V) in relation to biochemistry of vanadium

A selected set of 14 V(V) complexes was tested for toxicity and antitumor activity against L1210 murine leukemia, to examine the biological properties of peroxoheteroligand vanadates(V) of the formula (NH4)4[O(VO(O2)2)2], M3I[VO(O2)2C2O4], and MI[VO(O2)L], L = malate, citrate, iminodiacetate, nitrilotriacetate, and EDTA. The x-ray structure is known for five of these compounds. A relationship has been found between the chemical composition and the biological activity (antitumor activity-toxicity) of these complexes. Activity in the L1210 system is defined as greater than or equal to 25% increase in life span, and this was seen with (NH4)4[O(VO(O2)2)2]; M3[VO(O2)2(C2O4)]2H2O, M = K, NH4; and NH4[VO(O2)Malato]H2O. These observations are important for the biochemistry of vanadium. The special nature of electron transfer within the V(V)-peroxo moiety is proposed to be responsible for this phenomenon. Peroxo heteroligand vanadates(V) therefore represent a model system for studying some biochemical interactions of vanadium in living matter.

The Pharmacology and Clinical Effectiveness of Phenothiazines and Related Drugs for Managing Chemotherapy-induced Emesis

SummaryThe phenothiazines are a group of chemical agents with neuroleptic, antiemetic, antihistaminic, anticholinergic and sedative activities. Their main pharmacological response is determined by variations in the chemical structure of the side-chain at position 10 of the phenothiazine ring. The most widely used antiemetics contain a basic amino group incorporated into a piperazine ring. These compounds have decreased autonomic activity but the greatest extrapyramidal effects of all the phenothiazine subgroups. Their antiemetic action is primarily due to inhibition of dopaminergic transmission in the chemoreceptor trigger zone. They also demonstrate some effect at the vomiting centre through inhibition of peripheral autonomic afferent impulses via the vagus nerve.The phenothiazines are well absorbed orally although their bioavailability varies from 27 to 67% because of gut wall and first-pass liver metabolism. Plasma concentrations are increased 3- to 4-fold via the parenteral route of administration. They demonstrate a biphasic elimination curve with a distribution half-life of approximately 2 hours and an elimination half-life of 16 to 30 hours with wide intra- and interpatient variations in elimination. These drugs are highly lipophilic and protein bound. Their main route of elimination is via liver metabolism. There have been no specific correlations made between plasma concentration and efficacy, therefore individualisation of dosages is necessary.The phenothiazines demonstrate some degree of efficacy in the prevention of nausea and vomiting secondary to a variety of causes such as anaesthetics, radiation, cancer and drug toxicity. There is little difference between them in antiemetic effectiveness within a similar group of patients. For patients undergoing treatment with chemotherapeutic drugs having moderate to strong emetic stimuli, phenothiazines are significantly better than placebo in the prevention of emesis. In comparative trials, prochlorperazine is the most widely studied phenothiazine. It has been shown to be equally or less effective than droperidol, ‘low-dose’ metoclopramide, tetrahydrocannabinol, nabilone or ‘high-dose’ metoclopramide. Only a few patients preferred the phenothiazine to the newer antiemetics regardless of the outcome of the study. Other phenothiazines such as thiopropazate, thiethylperazine, metopimazine and fluphenazine in combination with nortriptyline have been shown to be significantly better than placebo in limited trials. Compounds structurally related to the phenothiazines such as chlorprothixene, the butyrophenones and domperidone show antiemetic effects superior to placebo and are at least as effective as the phenothiazines.Adverse reactions to the phenothiazines can be classified as extrapyramidal reactions, autonomic responses, hypersensitivity reactions and hormonal dysfunction. They may also enhance the effects of central nervous system depressants. Withdrawal of the drug is the most appropriate treatment for any of these side effects. Extrapyramidal reactions can be alleviated more quickly by the administration of diphenhydramine or certain anticholinergic drugs used in the treatment of Parkinsonism. In the vast majority of studies evaluating the antiemetic effect of the phenothiazines, the most common adverse reaction was oversedation.

Regulation of ribonucleotide reductase in mammalian cells by chemotherapeutic agents

The reductive conversion of ribonucleotides to deoxyribonucleotides is a prime target for the development of a cancer chemotherapeutic agent. A new series of inhibitors based on the polyhydroxy or polyamino aromatic ring has been developed. These compounds are effective ribonucleotide reductase inhibitors and possess antitumor activity if there are adjacent hydroxy or amino groups. The most effective enzyme inhibitor, 2,3,4-trihydroxybenzohydroxamic acid, is 145 times more effective than hydroxyurea. However, the best antileukemic compound is 3,4-dihydroxybenzohydroxamic acid, which increased the life span of L1210 leukemic mice more than 100%. Structure-activity studies have revealed that the hydroxamic moiety is not essential for activity. The polyhydroxybenzene derivatives reduced the pool sizes of all four deoxynucleotides. This contrasts with the action of hydroxyurea, which depletes only the deoxypurines. The mechanism of inhibition by this group of compounds appears to be related to their ability to trap free radicals, since there is good correspondence between reductase inhibition and free radical destruction. Some naturally occurring cytotoxic and neurological agents which have antineoplastic activity, dopa analogs and phenolic compounds isolated from mushrooms, bear a structural similarity to the new reductase inhibitors. We found that the dopa analogs were also inhibitory to ribonucleotide reductase. Another consequence of polyhydroxybenzoic acid derivative treatment is elevated reductase levels in the cell. Other cell cycle inhibitors that block from late G1 through early G2 also cause an enhanced level of ribonucleotide reductase. However, agents that block in early or mid-G1 or mid or late G2 and mitosis produce lower reductase levels. These data suggest that reductase synthesis is initiated at the G1/S transition point and this enhanced level of activity continues until late S or G2.

A prospective randomized comparison of protracted infusional 5‐fluorouracil with or without weekly bolus cisplatin in metastatic colorectal carcinoma. A mid‐atlantic oncology program study

One hundred eighty‐four patients with advanced measurable colorectal cancer not previously treated with chemotherapy were entered into a prospective randomized clinical trial by the Mid‐Atlantic Oncology Program (MAOP) to assess the value of weekly cisplatin (20 mg/m2) when added to a protracted schedule of 5‐fluorouracil (5‐FU) infusion (PIF) at 300 mg/m2/d for 10 weeks of every 12 weeks. The liver was the primary indicator lesion in approximately 75% of the study group. All tumor measurements required radiographic confirmation. The response rate in the PIF alone arm was 35% (29 of 83; 95% confidence interval [CI], 25% to 46%) compared with 33% (28 of 85; 95% CI, 23% to 44%) for the arm in which weekly cisplatin was added to PIF. The median survival times were 11.8 and 11.2 months in the two groups. Weekly cisplatin does not appear to add to the effectiveness of PIF in colorectal carcinoma.

Confidence regions for constrained optima in response-surface experiments.

The precision of the estimated optimum from a response-surface experiment is often indicated via a confidence region about the optimum. Sometimes, because of associated secondary responses, unconstrained optima produce unrealistic operating conditions, even when the true response surface is known. We consider confidence intervals for constrained optima for which the constraint function is known or separately estimated. An example from a cancer combination chemotherapy experiment illustrates the construction of such a region.

Activity of 3β-Hydroxy-13α-Amino-13,17-Seco-5α-Androstane-17-oic-13,17-Lactam(p-(bis(2-Chloroethyl)amino)-Phenyl)acetate (NSC 290205) in Murine Solid Tumors

The modified steroidal alkylating agent, 3 β -hydroxy-13α-amino-13,17-seco-5α-androstane-17-oic-13,17-lactam[p-[bis(2-chloroethyl)amino]-phenyl]acetate showed excellent activity in tr

Survival analysis of drug combinations using a hazards model with time-dependent covariates.

Hazard functions in cancer chemotherapeutic situations may not be proportional, so a nonproportional hazard model has been developed. The dose-response surface is explored by regression analysis of experimental data, and after the estimation of the underlying hazard function the quality of the fit of the model is assessed. Further, treatment levels may be optimized, and estimated survival distributions can be plotted for any treatment combination. In an example of two-drug treatment of murine L1210 leukemia, statistically significant nonproportionality is determined. Analysis permits extraction of potentially important information on drug interrelationships, which has been previously unavailable.

Clinical study of hydrazine sulfate in advanced cancer patients

SummaryTwenty-five patients with a variety of solid tumors were treated with hydrazine sulfate. Hydrazine was given orally in the form of 60 mg capsules from one to four times daily. No patient had a 50% reduction of tumor size. Subjective benefit was seen in three patients but it was of brief duration.

Confidence Interval about the Response at the Stationary Point of a Response Surface, with an Application to Preclinical Cancer Therapy

A method of calculating a confidence interval about the response at the stationary point of a response surface is presented. We show that the technique can also be used to calculate a confidence region about the location of the stationary point. The procedure is applied, via Coxs proportional-hazards model, to the analysis of survival data from a preclinical cancer chemotherapy experiment involving the combination of two drugs. It is seen that the results can be useful in determining the existence of a therapeutic synergism.